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Interplay between Mitophagy and inflammasome in Neurological Disorders Radhika Kesharwani, Deepaneeta Sarmah, Harpreet Kaur, Leela Mounika, Geetesh Verma, Veeresh Pabbala, Vignesh Kotian, Kiran Kalia, Anupom Borah, Kunjan R. Dave, Dileep R Yavagal, and Pallab Bhattacharya ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.9b00117 • Publication Date (Web): 27 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019
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ACS Chemical Neuroscience
Interplay between Mitophagy and inflammasome in Neurological Disorders
2 3
Radhika Kesharwani1†, Deepaneeta Sarmah1†, Harpreet Kaur1, Leela Mounika1,
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Geetesh Verma1, Veeresh Pabbala1, Vignesh Kotian1, Kiran Kalia1, Anupom Borah2,
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Kunjan R Dave3, Dileep R Yavagal3 and Pallab Bhattacharya1*
6 7 8 9 10 11 12 13
1Department
of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.2 Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.3Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
†Authors
have equal contribution
14 15 16
*Address of correspondence:
17 18 19 20 21 22 23 24 25
Pallab Bhattacharya, Ph.D Assistant Professor, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad Gandhinagar-382355, Gujarat, India. Email:
[email protected] [email protected] Phone: +91 79 66745555 Fax: +91 79 66745560
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List of Abbreviations
2
NLR - Nucleotide-binding oligomerization domain (NOD)-like receptors
3
ASC-Apoptosis speck-like protein containing a caspase recruitment domain (CARD)
4
NLRP3 – NLR family pyrin domain containing protein 3
5
NLRP1 - NLR family pyrin domain containing protein 1
6
NLRC4 - NLR family CARD domain containing protein 4
7
Atg– Autophagy related genes
8
ULK1 – Unc 51 like autophagy activating kinase 1
9
LC3 – Light chain kinase 3
10
GABARAP – GABA type A receptor associated protein
11
ROS – Reactive Oxygen Species
12
Bnip3 – BCL 2 interacting protein 3
13
FUNDC1 - FUN14 domain-containing protein 1
14
CK2 – Casein kinase 2
15
DRP1 – Dynamin related protein 1
16
OPA1 – Mitochondrial dynamin like GTPase
17
OMM – Outer mitochondrial membrane
18
IMM – Inner mitochondrial membrane
19
PINK1 - PTEN-induced putative kinase
20
CCCP – Carbonyl cyanide m-chlorophenyl hydrazone
21
MMP – Mitochondrial membrane potential
22
BAK - Bcl2 associated athano genes
23
PLEKHM1 - Pleckstrin homology domain containing protein family member 1
24
AMBRA – Autophagy and beclin 1 regulator 1
25
TAXBP1-Tax1-binding protein 1
26
SQSTM1-Sequestosome 1
27
NBR1-Neighbor of BRCA1 gene 1
28
PARL- Presenilin Associated Rhomboid Like
29
PTEN-L-Phosphatase and tensin homolog-L 2 ACS Paragon Plus Environment
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ASC-Apoptosis-Associated Speck-like Protein
2
CIITA-Class II Major Histocompatibility Complex Transactivator
3
IPAF-ICE-Protease Activating Factor
4
NAIP-NLR Family Apoptosis Inhibitory Protein
5
CARD-Caspase recruitment domains
6
ASIC- Acid-sensing ion channel 1
7
AMPK- AMP-activated protein kinase
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MAPK- Mitogen-activated protein kinase
9
NFKB- Nuclear factor kappa-light-chain-enhancer of activated B cells)
10
Nrf2- Nuclear factor (erythroid-derived 2)-like 2
11
MFF- MITOCHONDRIAL FISSION FACTOR;
12
Trx1-Thioredoxin-1
13
APC-Antigen presenting cell
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NR4A1- Nuclear Receptor Subfamily 4 Group A Member 1
15
JNK - C-Jun N-terminal kinase
16
TLR4-Toll-like receptor-4
17
ANSCs- Adult neural stem cells
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SVZ-Sub-ventricular zone
19
PPAR- Peroxisome proliferator-activated receptors
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PGC1-α- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
21
DFCP1- Double FYVE-containing protein 1
22
PTM-Post-translational modifications
23
TBK1- Serine/Threonine-Protein Kinase-1
24
VCP-Valosin-containing protein
25
HLA-Human leukocyte antigen
26
MttHtt- Mutant huntigtin gene
27
CCL4- C-C motif chemokine 4
28
IGF-1- Insulin-like growth factor 1
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HMGB-1- High mobility group box 1 protein 3 ACS Paragon Plus Environment
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PGF-2α - Prostaglandin F2α
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I-FABP- Fatty Acid Binding Protein 1
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DAMP- Damage-associated molecular patterns
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PAMP-Pathogen-associated molecular patterns
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Wdfy3- WD Repeat and FYVE Domain Containing 3
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NOS- Nitric oxide synthase
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Abstract
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Mitophagy and inflammasome have a pivotal role in the development of
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neuropathology. Molecular mechanisms behind mitophagy and inflammasome are
4
well understood, but lacunae prevail in understanding the crosstalk between them in
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various neurological disorders. As mitochondrial dysfunction is the prime event in
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neurodegeneration, the clearance of impaired mitochondria is one of the main task for
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maintaining cell integrity in majority of neuropathologies. Along with it, inflammasome
8
activation also plays a major role which is usually followed by mitochondrial
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dysfunction. The present review highlight basics of autophagy, mitophagy and
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inflammasome, the molecular mechanisms involved and more importantly it tries to
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elaborate the interplay between mitophagy and inflammasome in various neurological
12
disorders. This will help in upgrading the reader’s understanding in exploring the link
13
between mitophagy and inflammasome that has been dealt with limitations in past
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studies.
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Keywords: Cerebral ischemia, mitophagy, inflammasome, neurodegenerative
17
disorder, neuroinflammation
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1. Introduction
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The genesis of neurological disorders and their symptoms are different but at the
3
molecular level they have common attributes such as oxidative damage, aggregation
4
of misfolded proteins, mitochondrial dysfunction, impairment of autophagy, and
5
neuroinflammation1, 2. Impaired autophagy and neuroinflammation are the foremost
6
events involved in several neurological disorders3, 4. Misfolded proteins, such as α-
7
synuclein in Parkinson’s disease and amyloid β in Alzheimer’s disease, along with
8
oxidative stress play central role in the progression of neurodegeneration1. This
9
promotes activation of innate immune system to upregulate signaling of inflammasome
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complexes (NLRP3, NLRP1 and NLRC4) in the microglia for neuroinflammation.
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These mechanisms in some instances are also activated within the astrocytes and
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neurons that aggravates the disease5. In healthy cells, factors like nutrient deprivation,
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enhanced calcium influx and oxidative stress can lead to mitochondrial dysfunction6,
14
7.
15
known as mitophagy. This process of mitophagy gets dysregulated in neurological
16
diseases8.
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neuroinflammation and mitophagy, hence keeping this in mind, the present review
18
provides a brief overview of mitophagy and inflammasome, their mechanisms, and
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their associated cross talk in various neurological disorders.
Impaired mitochondria can be eliminated via specialized process of autophagy Recent
studies
report
that
there
is
a
connection
between
20 21
2. Autophagy and Mitophagy
22
Autophagy or self-eating is the process of degradation of impaired intracellular
23
components which is mediated by autophagy related proteins (Atg) and lysosomes 9.
24
Autophagy can be categorized into three types macroautophagy, microautophagy and
25
chaperon-mediated autophagy
26
comprises of five steps a) initiation of isolation membrane, b) elongation of isolation
27
membrane, c) formation of autophagosome, d) fusion of autophagosome and
28
lysosome and e) degradation of auto-phagolysosome 8. Autophagosome biogenesis
29
is regulated by unc51 like autophagy acting kinase 1 (ULK1), autophagy related
30
protein complex Atg16-Atg5-Atg12 and Atg 8 family proteins, while biogenesis and
31
maturation of autophagosome is regulated by microtubule-associated protein 1 light
32
chain 3 (LC3) and gamma-aminobutyric acid type 1 receptor (GABARAP). Soluble N-
33
ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) proteins
34
help in the fusion of autophagosome to lysosome and then the cargo is degraded by
10.
Mechanistically, the process of autophagy
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the lysosomal hydrolases
2
well as cargo selective. Non-selective autophagy plays major role during nutrient
3
deprivation in order to recycle essential nutrients from the cell, while cargo-selective
4
autophagy accounts for the removal of damaged organelles and aggregation prone
5
proteins that can be toxic for the cell 12. Cargo selective autophagy can be of various
6
types depending on the target such as aggrephagy (aggregated proteins), mitophagy
7
(mitochondria), ribophagy (ribosomes), peroxyphagy (peroxisomes), reticulophagy
8
(endoplasmic reticulum) and xenophagy (pathogens).
9
Selective autophagy of mitochondria is called mitophagy. It is a cellular quality control
10
process to maintain mitochondria’s integrity and its functional state8. The mechanism
11
of mitophagy was first identified in yeast and Uth1p gene was found to be an important
12
regulator of mitophagy
13
mitochondrial depolarisation favours sequestration of damaged mitochondria inside
14
the autophagosome which is followed by its fusion with lysosome that ultimately leads
15
to its degradation
16
promotes the clearance of damaged mitochondria which is responsible for the
17
generation of reactive oxygen species (ROS) as well as proapoptotic signals and
18
depletion of ATP
19
event associated with the development of pathology of several neurological ailments
20
like Parkinson’s disease, cerebral ischemia, Alzheimer’s disease and Amyotrophic
21
Lateral Sclerosis. Therefore, removal of damaged mitochondria is a prime requirement
22
for halting progression of neuropathology. Figure 1 illustrates the molecular
23
mechanisms behind mitophagy.
14.
15.
13.
Macroautophagy or autophagy can be non-selective as
Studies carried out in mammalian cells suggest that
Mitophagy plays central role in preventing cell death, as it
It is highly accepted that mitochondrial dysfunction is a major
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Figure 1: Illustration representing overview of molecular mechanisms behind
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mitophagy
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1) Mitochondrial depolarization followed by opening of mPTP caused by increased
5
levels of ROS 2) Recruitment of PINK1 from the cytosol to OMM due to mitochondrial
6
depolarization 3) Recruitment of Parkin to OMM induced by PINK1 4) Ubiquitination
7
of adaptor proteins (OPTN, p62, SQSTM1 and TAXBP1) present on OMM induced by
8
parkin 5) Tethering of ubiquitinated adaptor proteins with AMBRA1, a component of
9
autophagosomal membrane via LIR-binding domain 6) Fusion of autophagosome and
10
lysosome via interaction between HOPS and PLEKHM1 component of AP and Rab7
11
which is a component of lysosome 7) Degradation of damaged or superfluous
12
mitochondria via mitophagy.
13 14
3 Molecular mechanisms of mitophagy
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3.1 Receptor mediated mitophagy
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A) Bnip3/Nix: Bnip3 (BCL2/adenovirus E1B 19 kDa interacting protein) and Nix
17
(known as BNIP3L, a homolog of Bnip3) are pro-apoptotic mitochondrial proteins
18
where the former has Bcl-2 homology-3 domain (BH3) 16. The BH3 domain facilitates 8 ACS Paragon Plus Environment
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entry of Bnip3 to the outer mitochondrial membrane (OMM), which can be inhibited by
2
phosphorylation at C-terminus due to diminished interaction between bnip3 and OPA1
3
(a mitochondrial fusion regulator protein)17. Bnip3 regulates mitophagy during hypoxia
4
while
5
Bnip3/Nix is reported to be expressed in liver, kidney, brain, smooth muscles of
6
healthy cells but it is not present ubiquitously
7
many neurological disorders that modulates function of Bnip3/Nix
8
conditions promote attachment of hypoxia-inducible factor 1 (HIF-1) to the promoter
9
site of Bnip3/Nix, increasing expression of the same leading to mitophagy and thus
Nix regulates mitophagy during the development of erythroid lineage 19.
18.
Hypoxia is one of the key factors in
22,23.
20.
Hypoxic
10
reduces levels of ROS and mitigates apoptosis21,
11
Bnip3 also leads to enhanced mitophagy and thus cell death 24. Reports suggest that
12
Bnip3 is upregulated significantly in a delayed manner following cerebral ischemia in
13
neonatal stroke model, which is said to be responsible for cell death. It was observed
14
that Bnip3 gene silencing was able to prevent neuronal cell death following cerebral
15
ischemia 24.
16
B) FUNDC1 (FUN14 domain-containing protein 1): FUNDC1 is a protein present on
17
the OMM and is another important player of mitophagy
18
components within its structure, a 3-transmembrane domain and a N-terminal
19
cytosolic LIR-motif which binds with LC3 and GABARAP 25. It regulates autophagy via
20
recruitment of LC3 to mitochondria and by regulating mitochondrial fusion and fission
21
proteins, OPA1 and dynamin related protein 1 (DRP1) respectively 25, 26. Under normal
22
conditions, FUNDC1 is inhibited by negative phosphorylation by Src kinase at tyr18
23
and by casein kinase (CK2) at ser13 25,27. Hypoxic conditions or mitochondrial damage
24
activates PGAM5, which in turn activates CK2 and thus promotes phosphorylation.
25
LC3 then binds to damaged mitochondria, which then undergoes mitophagy
26
Recently it was reported that activation of Bcl-xl inhibits PGAM5 which leads to
27
inhibition of mitophagy28.
28
C) Prohibitin 2 (PHB2): Although the role of OMM proteins has been characterized
29
well during mitophagy, still extensive research is required to understand components
30
of inner mitochondrial membrane (IMM) that are involved in mitophagy. Recently,
31
PHB2 was characterized as a novel IMM protein and acts as a mitophagy receptor for
32
Parkin-mediated mitophagy in mammalian cells
33
rupture of OMM, that is achieved by PARK2 mediated ubiquitination and degradation
34
of OMM proteins followed by expression of PHB2 on OMM which further facilitates
29.
But excessive activation of
25.
It has two important
27.
Mitochondrial damage leads to
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binding of LC3 leading to mitophagy
2
achieved by USP14 inhibition. Results from co-immunoprecipitation assay showed
3
that interaction of PHB2 with LC3 depends on the activity of PARK2
4
it has been found that PHB2 does not interact with the GABA-type A receptor-
5
associated protein (GABARAP) and GABARAP-L2. As ubiquitin proteasome system
6
(UPS) is impaired in several neurodegenerative disorders, UPS may be targeted for
7
therapeutic purposes. Many de-ubiquitinating (DUB) enzymes are being explored.
8
USP14 is one of the DUB enzymes which regulates UPS negatively
9
supports that inhibition of USP14 leads to enhanced mitochondrial clearance. It also
10
Mitochondrial membrane rupture can be 31.
Interestingly,
32.
Studies
induces OMM rupture followed by interaction of PHB2-LC3 leading to mitophagy 30.
11 12
3.2 Parkin-PINK dependent mitophagy
13
PINK1 is PTEN-induced putative kinase which belongs to a family of Ser/Thr kinase
14
and thereby having kinase activity along with mitochondrial target sequence and it also
15
acts as a sensor for detection of polarized state of mitochondria 33, 34. While Parkin is
16
a E3-Ubiquitin ligase, PINK1 acts as an upstream regulator of PARKIN. This is
17
supported by a study in which it was found that PINK1-KO phenotype was rescued
18
with the overexpression of PARKIN but overexpression of PINK1 was not able to
19
rescue the PARKIN-KO phenotype in drosophila
20
mitochondria having proteins containing mitochondrial target sequence (MTS) and
21
single membrane spanning domain (SMSD) get entry into IMM through the
22
translocase of outer mitochondrial membrane (TOM) and translocase of inner
23
mitochondrial membrane (TIM) complex. Studies have reported two forms of PINK1,
24
a 64-kDa Full length PINK1 and a 52-kDa PINK137. Under normal conditions, the
25
former is present predominantly that enters the IMM by cleavage of MTS and is
26
converted into 60-kDa form. This is further cleaved by PARL (Presenilin associated
27
Rhomboid like protein) leading to formation of a 52-kDa form which is rapidly
28
processed and degraded by proteases and thus maintains the levels of PINK1 low and
29
inhibits mitophagy in healthy mitochondria 37, 38.
30
Under pathological conditions, mitochondria undergoes depolarization. To mimic the
31
same physiological conditions, studies have been carried out by using Carbonyl
32
cyanide m-chlorophenyl hydrazone (CCCP), which is a mitochondrial uncoupler39.
33
CCCP drastically reduces mitochondrial membrane potential (MMP), which blocks
34
transport of PINK1 to IMM and thus PINK1 will not be processed by PARL leading to
35, 36.
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In healthy cells, polarized
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accumulation of the 60-kDa form of PINK1 followed by recruitment of PARKIN37, 40.
2
This recruitment of PARKIN facilitates ubiquitination of OMM adaptor proteins like p62,
3
optineurin, SQSTM1, NBR1, TAXBP1 and this ubiquitination solely depends on the
4
TBK1 a Ser/Thrkinase that promotes phosphorylation of RAB7A, an activator of
5
mitophagy33,
6
autophagosome through their LIR motif (LC3-interacting region) to induce mitophagy
7
and promotes biogenesis of autophagosome via binding with AMBRA1 (an autophagy
8
promoting protein), followed by fusion of autophagosome with the lysosome via
9
autophagosomal proteins PLEKHM1 and HOPS and lysosomal protein-Rab7 and
39, 41.
These adaptor proteins followed by ubiquitination
42, 43.
targets
10
promotes mitophagy
11
was found to promote mitophagy independent of PINK1/PARKIN, via activation of
12
IKKα which in turn phosphorylates AMBRA, an activator of mitophagy
13
studies have suggested the role of PARKIN in apoptosis, as Parkin inhibits BAK, a
14
pro-apoptotic factor and thereby inhibits apoptosis and promotes clearance of
15
damaged mitochondria. Along with this it also promotes clearance of apoptotic
16
mitochondria and restricts their potential pro-inflammatory effect 44.
17
Mitochondrial outer membrane Rho GTPases Miro1/2 (Miro) are the adaptor proteins
18
that anchors mitochondria to motor proteins, which results in mitochondrial arrest
19
facilitating mitophagy. In healthy cells, Miro interacts with Parkin independent of
20
PINK1. However damaged mitochondria disrupt pool of Miro-Parkin due to
21
overexpression of PINK1 leading to ubiquitination and degradation of Miro and thus
22
impairs mitophagy
23
homolog-long (PTEN-L) prevents PINK1/PARKIN mediated mitophagy by preventing
24
translocation of Parkin as well as promotes phosphorylation of ubiquitin 45.
44.
Recently a novel ligase, identified as HUWE1 E3 ligase, 43.
Recent
Recently it was been identified that phosphatase and tensin
25 26
3. Inflammasomes
27
Inflammasomes are cytosolic complexes composed of three chief components:
28
sensor-NLRs, adaptor-ASC, effectors-pro-caspase1
29
types: canonical and non-canonical which activates caspase-1 and caspase-4,5,11
30
respectively 48-50. Innate immune response is the first line of immune defence against
31
invading pathogens and endogenous danger signals by pattern recognition receptors
32
(PRRs) through sensing the pathogen- and danger- associated molecular patterns
33
(PAMPs and DAMPs) 51, 52. Dendritic cells, microglia, astrocytes, neutrophils, epithelial
34
cells, macrophages and monocytes express huge amount of PRRs. PRRs are of
46, 47.
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Inflammasomes are of two
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various types including members of Toll-like receptors (TLRs), C-type lectins (CTLs),
2
nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) or absent in
3
melanoma 2 (AIM2)-like receptors (ALRs). TLRs are present on the extracellular
4
membranes, while NLRs are present in the cytosol. NLRs are mainly responsible for
5
formation of inflammasomes
6
NODs (NOD1, 2, NOD3/NLRC3, NOD4/NLRC5, NOD5/NLRX1, CIITA), NLRPs
7
(NLRP1–14,also called the NALPs) and ICE protein-activating factor (IPAF; NLRC4
8
and NAIP) 5. NLRs consists of a tripartite structure including C-terminal leucine-rich
9
repeats (LRRs) domain, NACHT or NOD (nucleotide-binding-oligomerization domain)
10
an intermediate domain and N-terminal effector domain can be pyrin domain (PYD) or
11
caspase recruitment domain (CARD)54. After sensing a stimuli, NLR undergoes
12
oligomerization by the interaction between their NACHT domains, then the
13
oligomerized NLR interacts with ASC through its PYD domain, followed by recruitment
14
of procaspase-1 by ASC via interaction of CARD/CARD. This is followed by cleavage
15
and activation of pro-caspase-1 to caspase-1, which further stimulates the maturation
16
of pro-inflammatory cytokines pro-interleukin 1β (IL-1β) and pro-IL-18 to active IL-1β
17
and IL-18
18
Gasdermin-D leading to pyroptosis and release of cytokines 56, 57. Indeed activation of
19
inflammasome is very essential in host-defence mechanism, although excessive
20
activation can damage the host cells. Recent study suggests that this excessive
21
inhibition is kept in check by Cullin1 (CUL1) component of the Skp1-Cullin1-F-box E3
22
ligase which binds with NRPL3 and promotes ubiquitination, not to degrade the protein
23
but to prevent activation of inflammasome
24
mitochondrial
25
inflammatory cytokines can also trigger mitochondrial damage60. So, it is quite
26
ambiguous that what comes first.
55.
53.
There are three subfamilies within the NLR family-
This is followed by maturation of cytokines and promotes cleavage of
damage
promote
activation
58.
of
Several studies suggest that inflammasomes59.
However,
27 28 29
4. Interplay between mitophagy and inflammasomes in neurological diseases A) Cerebral Ischemia
30
Activation of inflammasome is one of the events involved in cerebral ischemia5, 61. First
31
evidence of involvement of NLRP1 inflammasome in cerebral ischemia was reported
32
by Abulafia et al
33
receptor pyrin domain-containing 3 (NLRP3) inflammasome is reported to be
34
associated in cerebral ischemia. Apart from this, NLRP1, NLRC4, AIM2 are also
62.
The nucleotide binding domain leucine-rich repeat-containing
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involved in the inflammatory cascade in cerebral ischemia5. In cerebral ischemia levels
2
of ROS are elevated leading to NLRP3 inflammasome activation, which results in
3
release of IL-1β and IL-18 causing neuroinflammation3, 5, 63. NLRP1 is reported to be
4
activated in response to acid sensing ion channel (ASIC) activation, which further
5
release IL-1β and IL-18 and aggravate neuroinflammation 5. ATP depletion also
6
stimulates the activation of NLRP1 inflammasome via AMP-activated protein kinase
7
(AMPK). Nuclear factor kappa B (NFκB) and mitogen-activated factor (MAPK) lowers
8
the expression and activation of NLRP1 and NLRP3 inflammasomes under ischemic
9
condition 64.
10
NLRP3, NLRP1, NLRC4 and AIM2 inflammasomes are expressed and activated in
11
microglia and exacerbate the ischemic condition
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inflammasome complex regulates the inflammatory response, apoptotic and pyroptotic
13
death of microglial cells under ischemic condition
14
suppresses the activation of inflammasomes post ischemia
15
nicotine worsens cerebral ischemic condition by stimulating the inflammasome
16
activation via inhibition of ER-β signaling in post ischemic brain
17
that nuclear factor erythroid 2-related factor 2 (Nrf2) inhibits the activation of NLRP3
18
inflammasome by regulating the thioredoxin 1 (Trx1)/ thioredoxin interacting protein
19
(TXNIP) complex in the model of cerebral ischemia. It is suggested that under
20
oxidative stress conditions, Trx1/TXNIP complex dissociates and release TXNIP
21
which further stimulates the activation of NLRP3 inflammasome and Nrf2 acts as an
22
antioxidant agent which plays a protective role in the animal model of cerebral
23
ischemia 67.
24
Cerebral ischemia involves depletion in ATP and increase in AMP due to mitochondrial
25
dysfunction leading to
26
mitochondrial fission factor (MFF) which activates DRP1 and thus stimulates
27
mitochondrial fission and mitophagy
28
during reticulocyte maturation and in cerebral ischemia reperfusion-induced
29
mitophagy 69, 70. Acidic post-conditioning (APC) is a condition in which CO2 is inhaled
30
during reperfusion after cerebral ischemia leading to mild acidosis. It is reported that
31
APC maintains the mitochondrial membrane potential
32
sensor present in the mitochondria of neuronal cells which reduces the mitochondrial
33
membrane potential following oxidative stress 72. Findings suggest that APC alleviates
34
cerebral I/R injury via activation of mitophagy by recruiting PARK2 in mitochondria in
65.
65.
In addition to this, NLRC4 Estrogen receptor β (ER-β) 66.
66.
It is reported that It is also reported
activation of AMPK, promoting phosphorylation of 7, 68.
BNIP3L is mainly involved in mitophagy
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71.
ASIC1 is a main proton
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73.
Page 14 of 40
Peroxynitrite (ONOO-) is the main marker of
1
a mouse model of cerebral ischemia
2
reactive nitrogen species which promotes nitration of proteins. This further activates
3
mitochondrial fission and thus activates mitophagy
4
group A member 1 (NR4A1) is involved in regulating mitochondrial function. It is
5
reported that NR4A1 exacerbates the cerebral I/R injury by reducing the expression
6
of Mfn2 through MAPK-ERK-CREB signaling pathway
7
reperfusion injury the PINK1/Parkin/p62 pathway is activated to induce mitophagy
8
(Figure 2).
74.
Nuclear receptor subfamily 4
75.
In cerebral ischemia/ 76
9 10
Figure
2:
Illustration
representing
interplay
11
inflammasome in cerebral ischemia: Process of cerebral ischemia involves multiple
12
signalling pathways that activate or inhibit mitophagy (1-6) and inflammasome (7). 1)
13
Hypoxia occurring during cerebral ischemia increase levels of Bnip3/Nix via activation
14
of HIF-1, followed by activation of Beclin-1 which ultimately induces mitophagy 2)
15
Reperfusion injury following cerebral ischemia can produce ROS which also activates
16
mitophagy via PINK1/Parkin activation. 3) Decreased levels of ATP and increased
17
levels of AMP following mitochondrial dysfunction activates AMPK followed by fission 14 ACS Paragon Plus Environment
between
mitophagy
and
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1
of mitochondria due to activation of MFF and Drp1, a mitochondrial fission protein and
2
thus promotes mitophagy 4) Mitochondrial fission is also promoted by nitration of
3
proteins due to generation of RNS which activates mitophagy 5) Mitophagy is also
4
promoted by increased levels of LC3II, p62 and Beclin1 6) Acidic post-conditioning
5
(APC) activates PARK2 during ischemic condition and thus facilitates mitophagy 7)
6
Increased levels of ROS and activation of AMPK activates NLRP3 and NLRP1
7
respectively, which in turn activates Il-1β, IL-18 via activation of caspase-1 and
8
promotes neuroinflammation.
9
B) Parkinson’s disease (PD)
10 11
Oxidative stress and activation of both microglial cells and inflammasomes play a key
12
role in the pathology of PD as they promote neuroinflammation and neurodegeneration
13
77
14
which in turn activates c-Abl kinase which facilitates activation of NLRP3
15
inflammasomes
16
microglial cells which can also activate inflammasomes 79. Neurotoxins like rotenone,
17
MPTP, paraquat, dieldrin, manganese, salolinon, etc. increase levels of H2O2 which
18
activates JNK MAPK and subsequently activate caspase-1 and 3 leading to cell death
19
and promotes induction of PD
20
of α-synuclein via activation of inflammasome 81.
21
Crosstalk between caspase-1 and NLRP3 have been suggested by studies which
22
support that α-synuclein promotes activation of TLR2 which facilitates formation of
23
NLRP3 assembly and ultimately promotes synthesis of IL-1ß
24
levels of IL-1ß promotes generation of ROS and also promotes release of cathepsin-
25
B which finally upregulates NLRP3
26
synuclein also promotes activation of TLR4/NF-kB and NLRP3/caspase-1 signaling
27
mechanism in adult neural stem cells (ANSCs), which was confirmed by knockdown
28
of either caspase-1 or NLRP3 which inhibited proliferation of ANSCs
29
reported that miRNA-7 activates neurogenesis in subventricular zone (SVZ) via
30
inhibition of NLRP3/caspase-1 signalling mechanism in ANSCs 84.
31
Recently, researchers found that there was increased levels of NLRP3 within
32
mesencephalic neurons of PD patients
33
inflammation and death of dopaminergic neurons in which they have shown that
34
inhibition of hepatic inflammasomes by siNLRP3 (silencing RNA) leads to decreased
(Figure 3). More specifically, generation of ROS leads to increased oxidative stress 78.
ROS
also increases the activity of cathepsin-B in activated
80.
Activation of caspase-1 also promotes aggregation
79, 83.
82,83.
The increased
Furthermore, it has been reported that α-
85.
84.
It is also
Studies have described the role of liver
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Page 16 of 40
1
spreading of inflammatory cytokines to brain and thus halts the progression of
2
neuroinflammation and also the degeneration of dopaminergic neurons
3
Mitochondrial serine protease HtrA2 inhibits activation of NLRP3 and AIM2
4
inflammasomes which was confirmed by disruption of HtrA2 activity leading to
5
upregulation in NLRP3 and AIM2 inflammasomes in macrophages
6
demonstrated that MPTP promotes impairment in autophagy via induction of
7
PI3K/Akt/mTOR pathway which was confirmed by assessing levels of Beclin-1 and
8
LC3. Levels of which was found to be decreased 88. Many PPAR ß/delta agonists are
9
reported to have anti-inflammatory properties but mechanisms are yet to be explored
87.
86.
It has been
10
89.
11
agonist and it was found that it protected dopaminergic neurons in the midbrain,
12
increased levels of dopamine in the striatum and also inhibited activation of NLRP3
13
inflammasomes in astrocytes in a MPTP-mouse model of PD 89.
14
ß-arrestin-2 mediated dopamine D2-receptor (Drd2) signaling mechanism is
15
considered as potential anti-inflammatory target. In one study they used Drd2 agonist
16
and they found that it suppressed activation of NLRP3 inflammasome and also
17
decreased levels of caspase-1 and IL-1ß in MPTP-induced mouse model
18
and PARKIN are the widely-studied protein related to PD. PINK1-PARKIN pathway is
19
considered as most important pathway related to mitophagy
20
of mitochondria, mitochondrial rhomboid protease (PRAL) instead of PGAM5,
21
(phosphoglycerate mutase which promotes mitochondrial division by phosphorylation
22
of Drp1) cleaves PINK1 which leads to accumulation of PINK1 in the OMM
92.
23
Deficiency of PGAM5 leads to development of PD-like movement disorder
93.
24
Functions of PGAM5 are regulated by Syntaxin 17 which is a novel mitochondrial
25
protein mediating normal division of mitochondria under healthy conditions but upon
26
stimulation of mitophagy, syntaxin 17 detaches from Drp1 and binds with Atg14L
27
promoting formation of autophagosomes and also promotes elongation of
28
mitochondria. Upon mitophagy, cleaved PGAM5 promotes dephosphorylation of
29
FUNDC1 which promotes excessive breakdown of mitochondria
30
fusion is mediated by mitofusins and Opa1, while fission is mediated by Drp1
31
Mitochondrial fusion and fission are important for maintaining mitochondrial
32
homeostasis which is mediated by PINK1 and PARKIN, which was confirmed by one
33
study in which it was found that mitofusin (Mfn) is the mitochondrial fusion protein
34
which is ubiquitinated by PINK1 and PARKIN. Knockdown of Mfn1 and Mfn2 results
In a study researchers used GW501516, a selective and high-affinity PPAR ß/delta
16 ACS Paragon Plus Environment
91.
90.
PINK1
Upon depolarization
94.
Mitochondrial 95, 96.
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ACS Chemical Neuroscience
1
in altered MMP and inhibits recruitment of Parkin on OMM 97. Recently, it was identified
2
that retro-translocation of Mfn2 promotes detachment of mitochondria from ER
3
thereby, accelerates mitophagy
4
extract (GSE) preserves mitochondrial function, improved function of flight muscle,
5
prolonged life span via activation of mitophagy in PINK1 mutant drosophila model of
6
PD 99. Rotenone , a neurotoxin , used to develop model of PD induces autophagy and
7
mitophagy in PC12 cells100. Rotenone inhibits mitochondrial biogenesis and reduces
8
the mitochondrial membrane potential. PINK1 inhibits mitochondrial biogenesis by
9
inhibiting PGC1-α, which in turn inhibits PINK1/PARKIN protein and ultimately inhibits
10
mitophagy. Which indicates that mutual antagonism exists between PINK1/PARKIN
11
and PGC1-α.This maintains mitochondrial homeostasis in rotenone-induced
12
neurotoxicity 101.
98.
More recently, it was discovered that grape skin
13 14
Figure
3:
Illustration
15
inflammasome in Parkinson’s disease: Mitochondrial dysfunction in PD arises as a
16
result of exposure to neurotoxins. A) Increased ROS due to mitochondrial dysfunction
17
activates c-Abl and cathepsin B which further activates NLRP3 inflammasome. This
18
then
activates
Il-1β
representing
via
activation
interplay
of
between
caspase-1/3
17 ACS Paragon Plus Environment
and
mitophagy
finally
and
promotes
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1
neuroinflammation B) Increased levels of ROS as well as activation of caspase-1/3
2
induces the misfolding of wild-type α-synuclein to toxic α-synuclein which promotes
3
extensive degradation of mitochondria, promotes cleavage of PGAM5 instead of
4
PINK1 via activation of PARL. Further the cleaved PGAM5 dephosphorylates
5
FUNDC1 resulting into extensive mitochondrial breakdown C) Exposure to
6
neurotoxins also generates H2O2 which activates Jnk-MAPK pathway promoting
7
neuroinflammation via activation of caspase-1/3.
8
C) Alzheimer ’s disease
9
Inflammation plays a major role in the pathogenesis of AD, which is supported by
10
studies indicating enhanced levels of inflammatory cytokines in the brain sample of
11
AD patients
12
pathogenesis of AD, as a study found that NLRP3 enhances accumulation of Aβ
13
protein
14
overload of neuritic plaque in transgenic mice model of AD 104. Priming of microglia by
15
β-amyloid pathology resulted in activation of IL-1β leading to significant cognitive
16
decline as compared with wild type LPS-treated mice. But it was reported that priming
17
of microglia does not activate IL-1β or NFκB p65 nuclear translocation. But upon
18
secondary stimulation, it activates the IL-1β and also p62 nuclear translocation, from
19
this it was confirmed that secondary inflammatory insults induces cognitive
20
impairments specifically in in-vivo models 105.
21
Glial maturation factor (GMF) is a pro-inflammatory protein which activates glial cells
22
to stimulate neuroinflammation and neurodegeneration in AD. GMF is mainly present
23
and expressed in proximity to Aβ and tau in the temporal cortex of human AD brain.
24
Upon prolonged accumulation and aggregation of Aβ peptide, glial cells are activated
25
and secrete pro inflammatory cytokines. GMF enhances the activation of NLRP3
26
inflammasome and promotes neuroinflammation in AD 106. Although the link between
27
inflammasome and mitophagy in AD is yet not clearly understood, a link may be
28
supported by the study which suggests that mitophagy is impaired in AD resulting in
29
increased oxidative stress and deficiency of cellular energy triggering the
30
accumulation of Aβ peptide and tau protein, which further impairs mitophagy and
31
activates NLRP3 inflammasome
32
potential (MMP) due to which recruitment of PINK1/Parkin in the outer membrane of
33
dysfunctional mitochondria is halted 108. Accumulation of tau protein impairs mitophagy
34
by inhibiting the recruitment of Parkin in dysfunctional mitochondria by sequestering it
103.
102.
NLRP3 inflammasome was also found to be important in the
It is also reported that absence of NLRP3 inflammasome reduces the
107.
Tau protein increases mitochondrial membrane
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ACS Chemical Neuroscience
109.
1
in cytosol
Post-translational modifications (PTMs) in the tau protein leads to
2
impairment of mitophagy and this idea came after a study which suggests that NH2-
3
truncated tau protein promotes aberrant recruitment of Parkin and UCHL-1 modulator
4
of mitophagy which promotes deregulation of mitophagy 110. Aging is a natural process
5
which is associated with inflammation. This process is known as inflammaging. This
6
is mediated by inflammasome activation and is associated with the development of
7
deleterious conditions in the aging brain such as Alzheimer’s disease 111.
8 9
Fig 4: Illustration representing interplay between mitophagy and inflammasome
10
in Alzheimer’s disease: Mitochondrial dysfunction is the main pathological event
11
during AD which leads to accumulation of damaged mitochondria, which in turn
12
triggers production of ROS promoting accumulation of Aβ and Tau-proteins A) This in
13
turn activates microglia via release of glial maturation factor (GMF), followed by
14
activation of NLRP3-inflammasome which further promotes neuroinflammation. B)
15
Accumulation of Aβ and Tau-protein also impairs mitophagy by inhibiting recruitment
16
of PINK1/Parkin via two ways: either by increasing MMP or by directly promoting
17
sequestration of PINK1/Parkin in the cytosol.
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D) Amyotrophic Lateral Sclerosis
1 2
Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease involving
3
degeneration of both upper and lower motor neurons leading to motor and extra-motor
4
symptoms 112,113. Mitochondrial dysfunction and autophagy plays an important role in
5
ALS 114. Optineurin is an autophagy receptor that is recruited to the ubiquitinated OMM
6
proteins via its ubiquitin binding domain. On the other side it consists of light chain 3
7
(LC3) binding domain (LIR) which binds to LC3 for autophagosome formation favoured
8
by assistance of parkin 41. Optineurin momentarily binds to dysfunctional mitochondria
9
and allows the recruitment of double FYVE-containing protein 1 (DFCP1) for the
10
initiation of autophagosome formation and microtubule-associated protein LC3
11
recruitment 41.
12
In ALS there is mutation of optineurin E478G, as a result of which mitophagy is
13
subdued which exacerbates the pathology 41. Along with optineurin, ALS also involves
14
mutation of TANK-binding kinase 1 (TBK1) which phosphorylates optineurin in its
15
serine 177 residue and stimulates its binding to Atg8/LC3 and autophagic clearance
16
115.
17
required for binding of ubiquitin to LC3, which binds to LC3 via its LIR region. Studies
18
suggest that ALS-associated mutation in LIR region i.e. D337E, L341V reduces the
19
ability of binding of SQSTM1/p62 to LC3
20
containing protein (VCP) in the damaged outer mitochondrial membrane depends on
21
Parkin-mediated ubiquitination of damaged mitochondria 117. VCP undergoes mutation
22
during ALS, which leads to impairment of mitophagy 118.
23
Fibroblasts of ALS patients express C9orf72, which assists in protein synthesis,
24
undergoes mutation. This interacts with ULK1 and initiates autophagy
25
between inflammation and ALS was first established by Troost et. al., where they
26
found that brain of sporadic ALS patients expressed higher levels of MHC (major
27
histocompatibility complex) and HLA (human leucocyte antigens), which are important
28
components of inflammation
29
inflammation which were found to be activated in ALS-linked mutant SOD1 mice
30
Apart from these, reactive oxygen and nitrogen species were also found to be
31
upregulated. These reactive nitrogen are then converted into peroxynitrite leading to
32
protein nitration, which triggers the activation of caspase-1/inflammasome
33
involves accumulation of mutant superoxide dismutase 1 (SOD1)
34
sensed by ASC component of inflammasome as a result of which there is activation
Sequestosome 1 (SQSTM1) encodes for SQSTM1/p62 which is an adaptor protein
120.
116
(Figure 5). Localization of valosin-
119.
The link
NFкB and TLRs are important component of
20 ACS Paragon Plus Environment
123,
122.
121.
ALS
which can be
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ACS Chemical Neuroscience
124.
1
of caspase-1 and IL-1β in microglia which leads to neuroinflammation
Levels of
2
NLRP3 and other inflammasome components i.e. ASC, caspase-1, IL-1β and IL-18
3
were found to be overexpressed in the spinal cord of ALS-linked mutant SOD1 (G93A)
4
mice astrocytes and also in the tissue of ALS patient these levels are increased as
5
compared to healthy volunteers 125.
6 7
Figure 5: Illustration representing the role of genetic alteration and inflammatory
8
cascade in the development of ALS: A) Genetic alteration: 1) Mutations in TBK1
9
promotes phosphorylation of ubiquitinated adaptor proteins 2) E4784 mutation impairs
10
tethering of ubiquitinated adaptor proteins and AMBRA1 of AP and ultimately impairs
11
mitophagy 3) D337E and L341V mutation impairs autophagy via inhibiting interaction
12
of SQSTM1 and AMBRA1 of AP B) Inflammatory cascade: development of ALS
13
activates inflammasome directly via activation of 1) TLRs and NFkB 2) SOD1 or
14
indirectly via activation of 3) ROS and RNS which promotes nitration of protein.
15
Activation of inflammasome further activates caspase-1 followed by activation of Il-1β,
16
IL-18 and further triggers neuroinflammation.
17 18
E) Other neurological disorders 21 ACS Paragon Plus Environment
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Page 22 of 40
1 2
Other neurological conditions have also shown the involvement of mitophagy and
3
inflammasomes. These include epilepsy, Huntington’s disease, multiple sclerosis and
4
autism. Details of each have been summarised in table 1.
5
1. Huntington’s disease (HD)
6
Huntington’s disease is associated with the mutation of huntingtin gene (mtHtt) which
7
activates a cascade of detrimental events resulting in neurodegeneration.
8
Mitochondrial dysfunction is one of the major events involved in HD. VCP translocates
9
to mitochondria and interacts with UBXD1 leading to degradation of the OMM protein
10
MCL1, as a result of which mitophagy increases126,
11
mediated mitophagy128. Huntingtin facilitates the association of p62 with integral
12
autophagosome component, however due to mutation in huntingtin, mitophagy is
13
impaired129. mtHtt also triggers the activation of inflammasomes via NFkβ. This further
14
activates neuroinflammation by upregulating IL-6, IL-8 and TNF-α130. mtHtt inhibits the
15
phosphorylation induced by IGF-1/Akt, leading to neurotoxicity131, 132.
16
127
. mtHtt disturbs PINK/Parkin
2. Epilepsy
17
In case of refractory temporal lobe epilepsy with hippocampal sclerosis, LC3B was
18
found to be upregulated133. Evidence of role of inflammasome in epilepsy has been
19
reported in many studies suggesting that deficiency of COX and its product PGF-2α
20
may be responsible for increased susceptibility towards epilepsy134. Overexpression of
21
genes related to pro-inflammatory cytokines and NOS have been found in the
22
olfactory-bulb of frontal lobe epilepsy patients135. Epilepsy enhances release of HMGB-
23
1, an inflammatory cytokine which promotes neuroinflammation via activation of TLR-
24
4136.
25
3. Multiple sclerosis (MS)
26
Involvement of mitophagy and inflammasome have been documented in MS patients.
27
Increased levels of ATG5 and parkin have been reported in body fluids of MS
28
patients137. Active involvement of caspase 1 has also been reported in MS which
29
directly leads to inflammation138 139.
30
4. Autism
31
Wdfy3 is an autism risk gene ideally required for maintaining mitochondrial
32
homeostasis. Mutation of this gene in autism leads to inhibition of mitophagy 140. AIM2
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1
and NLRP3 have been found to be upregulated in the patients of autism, suggesting
2
the involvement of inflammasomes in autism141.
3 4 5
Table1: List of neurological diseases involving molecular mechanisms behind
6
mitophagy and inflammasome
7 Sr.No.
Neurological disease
Event
Target
Molecular mechanism
GAPDH
Abnormal interaction of polyglutamine repeats with the GAPDH prevents GAPDHmediated mitophagy
VCP
Mitophagy PINK1/Parkin
1
Huntington’s disease
Inflammasome
Presence of mtHtt facilitates interaction of VCP and UBXD1 results into degradation of OMM-protein MCL1 leads to uncontrolled mitophagy mtHtt impairs PINK1/Parkin-mediated mitophagy
C-terminal of Htt
Impaired p62-mediated mitophagy due to mutation in C-terminal of Htt
NFkB
mtHtt activates NFkB cascade and upregulates IL-6,IL-8,TNF-α and promotes neuroinflammation
CCL4 and MMP9
Upregulated in the brains of HD patients
IGF-1/Akt
mtHtt mediates neurotoxicity via inhibitory effect on phosphorylation induced by IGF-1/Akt
23 ACS Paragon Plus Environment
Reference
142
126, 127
128
129
130
143
131, 132
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LC3B Mitophagy
PGF-2α
Epilepsy Inflammasome
2
Mitophagy
3
Page 24 of 40
LC3B upregulated in case of rTLE with hippocampal sclerosis Lack of PGF-2α increased susceptibility to the seizures in immature brain
Proinflammatory cytokines and NOS genes
Upregulated in olfactory bulbs of FLE patients
HMGB-1
Epilepsy promotes release of HMGB-1, an inflammatory cytokine, activates TLR-4 leads to neuroinflammation
ATG5 and Parkin
ATG5 and Parkin activates mitophagy
Caspase-1
Caspase-1 activation followed by activation of glial inflammasomes and pyroptosis in MS
Multiple sclerosis
133
134
135
136
137
138
Inflammasome
Mitophagy
4
Autism Inflammasome
ASC and Caspase-1
MS promotes activation of inflammasome via activation of ASC and caspase-1
Wdfy3
Mutation in Wdfy3 leads to inhibition of mitophagy
AIM2 and NLRP3
Upregulated in case of ASD patients, responsible for inflammasome activation
I-FABP
Compromised GI permeability promotes release of I-FABP followed by release of ATP, an activator of DAMP and activates inflammasome
139
140
141
141
1 2
5. Concluding Remarks
3
Mitophagy and inflammasome activation are two main cellular events involved in
4
several neurological diseases. The former is important for elimination of damaged 24 ACS Paragon Plus Environment
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1
mitochondria while the later provides a molecular platform for activation of caspase-1
2
which secretes IL-1β in response to various insults leading to neuroinflammation in
3
various neurological diseases. Each and every neurological disease comes with its
4
unique pathogenesis. Although, mitophagy and inflammasome have been implicated
5
in various neurological diseases like AD, PD, HD, MS, etc. The interplay between the
6
two in various neurological disorders is yet not clear. Thus, here we have tried to find
7
the link between inflammasome and mitophagy in different neurological diseases that
8
was not put forward effectively. By developing some novel therapeutics against the
9
target which regulates mitophagy and inflammasome activation, one may pave a way
10
to halt the progression of neurological disorders.
11
6.
12
Authors acknowledge Department of Science and Technology (DST),Govt.of India for
13
their financial support through a grant (SB/YS/LS-196/2014), International Society for
14
Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals, Ministry
15
of Chemical and Fertilizers, Govt of India and National Institute of Pharmaceutical
16
Education and Research (NIPER) Ahmedabad, Gandhinagar, India.
17
Acknowledgements
7. Conflict of Interest
18
The authors declare that they have no conflicts of interest.
19
Authors Contributions:
20
RK, DS, PB, KD and DY conceived and designed the study. RK,DS,PB,
21
KD,AB,HK,LM,GV,VP,VK, KK and DY outlined the performed rigorous literature
22
search. RK, DS, PB, KD, KK, DY conceived and designed the figures and images. RK,
23
DS, PB, KD, KK, and DY wrote the manuscript.
24
References
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Inflammasome
Mitophagy
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Cerebral Ischemia Multiple Sclerosis Parkinson’s Disease Alzheimer’s Disease Amyotrophic Lateral Sclerosis Autism Epilepsy Huntington’s Disease
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