Exosomes in Parkinson's disease: current perspectives and future

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Exosomes in Parkinson’s disease: current perspectives and future challenges Lin Yuan, and Jia-Yi Li ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00469 • Publication Date (Web): 21 Jan 2019 Downloaded from http://pubs.acs.org on January 22, 2019

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ACS Chemical Neuroscience

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Exosomes in Parkinson’s disease: current perspectives and future challenges

2

Lin Yuan1 and Jia-Yi Li1, 2*.

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1 Institute

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2

6

Experimental Medical Science, Lund University, BMC A10, 22184 Lund, Sweden

of Health Science, China Medical University, Shenyang 110122, China.

Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of

7 8 9

*Correspondence:

10

[email protected]

11

[email protected]

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1

ACS Paragon Plus Environment

ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract

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Exosomes, which are lipid bilayer membrane vesicles, have been implicated as

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carriers of biological macromolecules. In recent years, the functions of exosomes in

17

the spreading of pathological conversion of proteins among neurons have drawn

18

particular attention in Parkinson’s disease research. Extracellular α-synuclein is

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proven to be associated with exosomes in vivo and in vitro. The contents of these

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exosomes may be altered during the pathological and clinical processes, serving as a

21

potential target for biomarker development in Parkinson’s disease. This review

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highlights the current understanding of biogenesis and pathophysiological roles of

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exosomes. Meanwhile, exosomes are promising delivery vehicles. Artificial exosomes

24

can be loaded with defined therapeutically active molecules, such as drugs, small

25

interfering RNAs, long non-coding RNAs and proteins to the brain, ensuring the

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site-specific targeting strategy to the recipient cells. Therefore, we will also discuss

27

the potential applications of exosomes in developing modified exosome-based drug

28

carrier systems to halt the pathologic propagation of Parkinson’s disease.

29 30

Key words: exosomes, Parkinson’s disease, α-synuclein

31

2


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1. Introduction

33

Parkinson’s disease (PD) is the second most common neurodegenerative disorder,

34

after Alzheimer's disease (AD) in slow-progressive neurodegenerative diseases.1,2 PD

35

is mainly known by a wide spectrum of motor symptoms, such as tremors,

36

bradykinesia, rigidity and postural instability. Before the clinical phase of PD,

37

hyposmia, disturbed sleep, and constipation are the major symptoms in the prodromal

38

phase of PD.3 It has been hypothesized that the intestinal enteric system and olfactory

39

bulbs may be the initial sites during disease development and progression. The

40

disease process varies epidemiologically in both genetic and environmental aspects.

41

Histopathologically, one of neuropathological hallmarks of PD is abnormal

42

aggregation of the synaptic protein α-synuclein (α-syn), termed Lewy bodies (LBs)

43

and Lewy neuritis (LNs) in surviving neurons.4,5 In addition to its involvement in the

44

pathogenesis of PD, extracellular α-syn has been considered as a potential biomarker

45

of clinical diagnosis of disease progression.6,7

46

Recent findings have demonstrated that aggregated α-syn is transmissible

47

transneuronally.8,9 The pathogenic forms of α-syn could be secreted into the

48

extracellular spaces, and spread into nearby neurons and non-neuronal cells.

49

However, the precise molecular mechanisms of α-syn secretion and transmission

50

among adjacent cells are still poorly understood. Recently, a large body of evidence

51

has supported extracellular vesicles (EVs) as the paracrine messenger for pathogenic

52

protein transmission, particularly exosomes. Based on intracellular origins, EVs are

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categorized into different classes of vesicles: apoptotic bodies, microvesicles,

54

exosomes, etc.10 Each kind of membranous vesicle has its own characteristics, such as

55

difference in size and membrane-associated or matrix-contained marker proteins.

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Apoptotic bodies are defined as extracellular vesicles ranging from 50 to 5000 nm

57

diameter in size, containing DNA, RNA and proteins.11 During apoptosis, the contents

58

released from apoptotic bodies are delivered to macrophages, resulting in cell

59

engulfing.12,13 Microvesicles have sizes ranging from 50 to 1000 nm and are produced

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by budding from the plasma membrane (PM) of a variety of cell types.10 Within

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multivesicular bodies (MVBs), the intraluminal vesicles (ILVs) can be formed by 3



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inward budding and released into the extracellular environment, producing exosomes,

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which are different from microvesicles according to their size and intracellular

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origin.14

65

Exosomes are nano-sized extracellular vesicles with a diameter of 40-100 nm and

66

display a cup-shaped morphology under transmission electron microscope (TEM).15

67

Several defined biomarkers for exosomes have been identified, such as CD63, CD81

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(tetraspanins), TSG101 and ALIX.16 Exosomes are secreted from various kinds of

69

cells and released into the extracellular space, isolated from bodily fluids, including

70

plasma, saliva, milk, urine and cerebrospinal fluid (CSF).17-19 These exosomes are

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defined as delivery shuttles for the cargoes in a biological system, and many

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pathogenic forms of proteins have been proven to be associated with exosomes. For

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example, amyloid-β peptide (Aβ) and tau in AD,20, 21 tau22 and α-syn23-26 in PD, prion

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proteins in the scrapie form27 have been identified to be propagated via exosomes.

75

These “nanospheres” with a bilayer membrane act as significant contributors to

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pathogenic neurons in PD. Actually, distinct circulating exosome subpopulations have

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been identified in the sera of patients with PD.28 Additionally, there is evidence that

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exosomal α-syn can more efficiently spread from a donor cell to recipient cells than

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free α-syn.24 A similar mechanism of regulation has been shown that exosomes

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promote PD progression. Vassilis et al. conducted a study to increase the number of

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brain

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exosome-associated α-syn oligomers. Such effects induced propagation of α-syn in

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glucocerebrosidase gene (GBA)-associated PD.29 Therefore, therapeutic intervention

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with different strategies of exosomes in the context of PD requires a profound

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knowledge of exosomal biogenesis, as well as the variety of cargos, which are by

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exosomes on PD in progression. It appears that modulating exosomes has a promising

87

prospects in PD therapy, and many articles have already summarized the features of

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exosomes in PD development and treatment.30,31 In this review, we briefly elaborate

89

on the biogenesis of exosomes and the multiple roles of exosomes for intercellular

90

transport of pathological α-syn, and aim to further highlight its potential therapeutic

91

applications in PD.

exosomes

via

glucocerebrosidase

(GCase)

inhibition,

as

well

as

4


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92 93

2. Exosome biogenesis and function

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2.1 Biogenesis

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The biogenesis of exosomes begins with the endosomal trafficking pathway and

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closely connects with the endosomal system. The endosomal system contains primary

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endocytic vesicles, early endosomes and MVB.32 The process of exosome formation

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can be divided into three stages (Figure 1). The formation of “early” endosomes (EEs)

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is identified as the first step. Proteins on the plasma membrane are transferred to the

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surface of the EEs. Rab5GTPases are the biomarkers of these EEs. EEs are closely

101

located at the cell membrane, and the functional roles of the EEs are to sort the

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cargoes for recycling back from the PM, followed by targeting to the endocytic

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recycling compartment (positive for Rab11), or transferring to late endosomes,

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identified by Rab7 and Rab9. During the second stage, the limiting membrane can

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invaginate and form ILVs, which accumulate in the lumen of the late endosome.

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Because the late endosome can contain many ILVs, it is also called the MVB. The

107

third step contains two pathways for the contents in the MVBs. The subsequent fusion

108

of the MVB with the PM releases ILVs into the extracellular space,33, 34 generating

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exosomes. It is worth noting that not all vesicles within the MVBs are sorted for

110

release as exosomes, one parts of MVBs are carried to the lysosomal degradation

111

pathway where the exosomes are removed as debris and recycled for cellular use. The

112

underlying mechanisms for certain MVBs being fused with the PM for releasing

113

exosomes or sending them to lysosomes for degradation35 is still unknown. Compared

114

with degradative MVBs, MVBs enriched with cholesterol fuse preferentially with the

115

PM.36 Another study indicated that integration of membrane proteins designates

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MVBs to lysosomal degradation.37 The molecular mechanism for exosome biogenesis

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could be divided into two types according to (in-) dependence on the

118

endosomal-sorting

119

ESCRT-dependent pathway combines syntenin with ALIX and bridges VPS32, VPS4

120

and TSG101. These proteins are usually condensed as special protein markers about

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ESCRT for exosomes, while tetraspanins, such as CD9, CD63 and CD81 are tightly

complex

response

for

transport

(ESCRT).

The

classic

5



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associated with the ESCRT-independent system.38 The evidence shows that MVB

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formation is independent from ESCRT system and nSMase2. Rab11 and Rab27,

124

members of the RabGTPase family, are involved in MVB trafficking and can

125

influence exosome secretion.39 The molecular mechanism of MVB fusion with the

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PM remains to be further clarified. The selective process of exosome-uptake between

127

the exosomes and recipient cells is mainly categorized as follows: exosomal ligands

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bind to the recipient cell surface receptor directly,40 internalized by endocytosis41 and

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fused to the target cell.42 In view of the complex mechanism of the biogenesis, release

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and uptake of exosomes, a large number of studies have focused on the trafficking of

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exosomes to inhibit the number of exosomes, aimed at weakening their functions and

132

be used for neurodegenerative disease, tumor or other disease therapies.

133 134

2.2 Exosomes in pathogenic transmission

135

Recent studies have suggested the importance of exosomes for cell to cell

136

communication in the central nervous system (CNS).34, 43 In the CNS, most cell types

137

can release exosomes, including neurons and glial cells (microglia and astrocytes).44

138

Exosomes are prominently involved in transmitting reciprocal signals between glia

139

and neurons (Figure 2). The cross-talk of exosomes between neurons and glial cells

140

contributes to the progression of PD. It is possible that the plasma exosomal α-syn is

141

derived from CNS.26 Furthermore, previous studies have demonstrated that α-syn

142

aggregates are released via exosomes and spread to other neuronal cells,45 forming

143

α-syn aggregates in the recipient neurons. Emmanouilidou et al showed that neuronal

144

cell-derived exosomes induced recipient cell death.25 Of interest, injured neurons can

145

release a much greater quantity of exosomes than less active neurons46, 47 and much

146

more neuron-derived exosomes containing fibrillar α-syn and ubiquitinated proteins

147

thus accelerating the transmission of pathological α-syn among neurons,48 and even

148

glia. To decrease α-syn accumulation in neurons, glia can uptake extracellular α-syn.

149

However, extensive uptake of α-syn can generate glial inclusions and initiate

150

inflammatory reaction.

151

It has been indicated that microglia can be induced to release exosomes by 6


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α-syn.49 As tissue-resident macrophages in the CNS, the functions of microglia are

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crucial for inflammatory responses against pathogens in neurodegenerative diseases.

154

Most notably, inflammatory factors, such as cytokines and chemokines, could be

155

transmitted between neurons and glia via exosomes derived from microglia.50 α-syn

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activates the secretion of neuron-derived exosomes, and the isolated exosomes

157

containing high levels of MHC-II and TNF-α lead to increased BV-2 cell apoptosis.49

158

However, exosomes derived from microglia containing inflammatory factors can alter

159

the

160

neurodegeneration.51, 52

balance

of

brain

homeostasis

and

accelerate

the

progression

of

161

It is worth mentioning that astrocytes are responsible for synaptic structural

162

integrity, synaptic transmission and neuronal function.53 Recently, astrocytes in the

163

CNS have been reported to secrete exosomes.54 It is believed that exosomes act as

164

carriers spreading pathology in neurodegenerative disorders.55 In response to

165

neuro-inflammation in the CNS, astrocytes release cytokines, chemokines and other

166

neurotoxic substances. In mouse models of AD, astrocytic activation is exhibited.

167

These activated astrocytes localized around amyloid plaques, in association with

168

elevated levels of TNF-α，IFN-γ，IL-1β and MCP-1.56 Furthermore, these cytokines

169

are known to be neurotoxic and are speculated to participate in neuro-inflammation in

170

PD.57 Additionally, Ranjit et al. have reported that astrocytes can release exosomes.58

171

Astrocyte-derived exosomes accelerate the inflammatory factors to transmit between

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the glia and neurons. This fact urges us to deduce that exosomes could also play a

173

crucial role in pathological α-syn propagation in neuronal and glial cells.

174 175

3 Exosomes as vehicles for nucleic acids

176

Exosomes can are known to transport nucleic acids to target cells, such as RNAs.

177

These RNAs induce genetic modifications in the PD’s pathogenic processes.59

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Considering the features of exosomes, delivering modified and therapeutic genetic

179

materials via exosomes to regulate the balance of gene expression is of great interest

180

scientifically and therapeutically. Here we will briefly summarize current thoughts on 7



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RNAs within exosomes of PD and the modification of these nanoparticles for the

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development of therapeutic strategies.

183 184

3.1 siRNAs

185

Small interfering RNAs (siRNAs), with great therapeutic potential, are involved

186

in silencing gene expression through targeting mRNA, resulting in mRNA

187

degradation during post-transcription.60 siRNAs are known as a modification

188

technology and are a promising therapeutic alternative for diseases in genetic therapy.

189

However, siRNAs have also been limited in the treatment of neurological disorders

190

due to their poor bioavailability in the systemic circulation. Thus, the delivery method

191

for siRNAs needs to be improved for clinical practice.

192

Exosomes are ideal delivery carriers for unstable therapeutic molecules.61 To

193

evaluate the security of exosomes as therapeutic shuttles, Alvarez-Erviti et al.

194

demonstrated that siRNAs could be transported to the brains of mice via exosomes.62

195

Subsequently, human exosomes were used to carry siRNAs to T cells and

196

monocytes.63 Moreover, accumulating evidence identified that exosomes loaded with

197

a variety of cargoes play pivotal roles in cell-to-cell communication.64 Based on their

198

characteristics, exosomes are being exploited as vehicles for siRNA delivery

199

shuttles.65 Exosomal drug formulations with siRNAs have been applied in

200

neurodegenerative disorders, such as PD. To evaluate the potential method for PD

201

treatments, Cooper and colleagues assessed the transport ability of exosomes loaded

202

with siRNAs to down-regulate α-syn in the brains of mice. Intraneuronal protein

203

aggregates

204

neurons in PD mice.59 Similarly, Marie et al reported that exosomes delivered

205

hydrophobically modified siRNA to the brain targeting huntingtin mRNA

206

efficiently.66 These studies indicated that exosomes deliver siRNAs successfully to the

207

brain, presenting promising advantages for the treatment of neurodegenerative

208

disorders.

were

reduced

significantly

in

dopaminergic

209 210

3.2 miRNAs 8


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211

microRNAs (miRNAs), as post-transcriptional regulators, inhibiting translation

212

via sequence-specific targeting of the 3’ untranslated region of mRNAs, regulating

213

cell proliferation, cell differentiation, and apoptosis.67 Abnormal expression of

214

miRNAs is functionally linked to the major features and risk factors of PD, including

215

α-syn overexpression, LB formation and neuronal apoptosis.68,1,69 miRNA132 target

216

sites are MeCP2 and SIRT1, and downregulation of miRNA132 is involved in the

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molecular mechanisms of learning, memory, neuronal maturation and protection.70

218

Sustained dysregulation of miRNAs has been implicated in neurodegenerative

219

disorders;71 Kim et al. showed that miRNA-133b was down-regulated in the midbrain

220

of PD patients,72 indicating that miRNAs may affect PD pathogenic processes. Studies

221

into next-generation sequencing have indicated that alterations of miRNAs are

222

correlated with clinical features in PD.73 Abnormal expression of miRNAs has

223

significant effects on PD, which provides the basis of exosomal miRNAs in PD.

224

Abnormal expression of endogenous miRNAs packaged into exosomes has been

225

detected in PD. Gui and co-authors developed a profiling for exosomal miRNAs,

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which were differentially expressed in exosomes derived from the CSF of PD

227

patients. Compared with healthy subjects, miRNA expression analysis of CSF-derived

228

exosomes suggested that 11 miRNAs were down-regulated and 16 miRNAs were

229

up-regulated in PD (Table 1). In further verification, miR-1 and miR-19b-3p were

230

shown to be down-regulated while miR-153, miR-409-3p, miR-10a-5p and let-7g-3p

231

were up-regulated significantly in CSF-derived exosomes of PD patients.74

232

Additionally, 24 exosomal miRNAs were evaluated in serum samples from patients

233

with PD, confirming that miRNA19b, miRNA195 and miRNA24 could be used as

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potential candidates to diagnose PD, indicating the specificity and sensitivity to

235

distinguish PD patients from healthy individuals with exosomal miRNAs.75

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Furthermore, the authors predicted the gene target sites of these three

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exosomal-miRNAs using the Targetscan tool; PARK2/LRRK2-miRNA19b and

238

ATP13A2-miRNA24/miRNA195 were correlated with the neurodegenerative

239

processes in PD.75, 76 This evidence revealed that miRNAs may present as potential

240

biomarkers with high specificity and sensitivity for PD diagnosis during the early 9



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stage.74 However, further work is necessary to modify the exosomes to deliver

242

therapeutic nucleic acids which can regulate the abnormal expression of these

243

miRNAs in the PD process.

244 245

Table 1. The differential miRNA expression in exosomes derived from the CSF of PD

246

patients74 Up-regulation

Down-regulation

hsa-mir-103a, hsa-mir-30b, hsa-mir-16-2, hsa-mir-1,

hsa-mir-22,

hsa-mir-29,

hsa-mir-26a,

hsa-mir-331-5p, hsa-mir-374, hsa-mir-119a, hsa-mir-126,

hsa-mir-153,

hsa-mir-132-5p, hsa-mir-151, hsa-mir-28, hsa-mir-301a,

hsa-mir-485-5p,

hsa-mir-127-3p, hsa-mir-19b-3p, hsa-mir-29c

hsa-mir-409-3p, hsa-mir-370, hsa-mir-873-3p,

hsa-mir-433, hsa-let-7g-3p, hsa-mir-136-3p,

hsa-mir-10a-5p 247 248

3.3 lncRNAs

249

Long non-coding RNAs (lncRNAs) have been defined as transcripts of more

250

than 200 nucleotides without protein-coding potential. lncRNAs regulate gene

251

expression at the translation level or epigenetic level, thereby changing the cellular

252

response to a variety of stimuli. Dysfunction of lncRNAs occurs in various

253

neuro-associated diseases, including neuropsychiatric disorders,77 autism,78 AD79 and

254

PD.80 Therefore, lncRNA dysfunction may be a major feature of these diseases. Many

255

lncRNAs have been shown to be involved in the development of PD (Table 2).

256

Microarray analysis indicated that paraquat and MPTP exposure induces alterations of

257

the lncRNA expression profile in mice,81 which suggests that lncRNAs play important

258

roles in the development of PD via interaction with each other. The lncRNA, NEAT1,

259

which is associated with pathological changes in the brain and nervous system, could

260

enhance autophagy by stabilizing PINK1 protein in PD mice.82

10


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261

High expression of the lncRNA, HOTAIR, an approximately 2.2 kb long

262

noncoding RNA transcribed from the HOXC locus, promotes MPTP-induced lesion

263

via up-regulating the expression of LRRK2.83,84 The expression levels of

264

lincRNA-p21, MALAT1, SNHG1, and TncRNA were significantly increased in the

265

PD brains.80 Specially, lncRNA MALAT1 is shown to regulate the apoptosis of

266

MPP+-treated cells via the lncRNA MALAT1/miR-205-5p or miR-124 axis.85,86

267

Furthermore, MALAT1 can interact with the serine/arginine splicing factor to

268

regulate synaptic-related gene expression in cultured hippocampal neurons, thus

269

regulating the synaptic density.87 These findings suggest that modulation of some

270

lncRNAs could be used as the effective disease-modifying strategy for PD therapy.

271

Although PD may be modulated by lncRNAs, as indicated above, the role of

272

exosomal lncRNAs thus affecting PD development is largely unknown. Up to date, no

273

evidence has been reported on exosomal lncRNAs in PD. Nonetheless, the researches

274

on the biological processes of exosome-associated lncRNAs in tumors have already

275

begun to emerge. For example, exosomal lncRNA ATB play a crucial role in

276

modulating the glioma microenvironment. They found glioma cell-derived exosomal

277

lncRNA ATB activated astrocytes by suppression of microRNA-204-3p promoted the

278

migration and invasion of glioma cells.88 In another study, lncRNA SNHG14 was

279

found to be enriched in exosomes and promoted trastuzumab chemoresistance in

280

breast cancer.89 These intriguing examples of the roles about exosomal lncRNAs in

281

tumors indicate the non-cell autonomous effects of lncRNAs, which mediated by

282

exosomes .

283

Exosomal lncRNAs derived from various bodily fluids could be internalized by

284

different types of recipient cells. As delivery vehicles, lncRNAs could be loaded with

285

mRNAs and other small molecules into the exosomes. Combined with the exosomal

286

characteristics of biocompatibility and bio-distribution, modified lncRNAs loaded

287

into exosomal could be a potential therapeutic method. Therefore, it is of importance

288

to explore the involvement and regulatory functions of potential lncRNAs associated

289

with exosomes for PD pathogenesis.

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291

Table 2. Mechanism of lncRNA exerts in PD

292

lncRNA

Experimental

Mechanisms (Reference)

objects NEAT1

mouse

NEAT1 over-expression induces autophagy and stabilizes PINK1 protein82

HOTAIR

mouse

Enhancing

HOTAIR

upregulates

LRRK2

expression83, 84 MALAT1

MAPT-AS

mouse,

Increasing MALAT1 inhibites α-synuclein

SH-SY5Y cells

protein expression80,85,86

80 brain tissue

MAPT-AS1 knockdown induces methylation of the endogenous MAPT promoter 90

1 AL049437

Substantia nigra Reduction

of

of PD patients, viability,

mitochondrial

SH-SY5Y cell

AL049437

increases

cell

transmembrane

potential, mitochondrial mass, and tyrosine hydroxylase secretion91

AK021630

Substantia nigra Reduction

of

of PD patients, viability,

mitochondrial

SH-SY5Y cell

AK021630

decreases

cell

transmembrane

potential, mitochondrial mass, and tyrosine hydroxylase secretion91

AS Uchl1

MN9D cells

AS Uchl1 RNA acts as a component of Nurr1-dependent gene network and target of cellular stress92

SNHG1

BV2 microglial SNHG1 promotes neuroinflammation in the cells,

Primary pathogenesis of PD modulating miR-7/NLRP3

cortical neurons

pathway2

293 294 295

3.4 ceRNAs Recent reports have described that diverse RNA transcripts, including

12


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296

protein-coding messenger RNAs and non-coding RNAs, such as long non-coding

297

RNAs, pseudogenes and circular RNAs, act as competing endogenous RNAs

298

(ceRNAs).93 ceRNAs were considered as a novel category of regulatory RNAs: these

299

transcripts compete with mRNAs for miRNAs, working as molecular “sponges” and

300

thus influencing the expression level of mRNAs. Understanding the novel RNA

301

crosstalk will contribute to significant insight into gene regulatory networks and

302

identify optimal candidates as potential diagnostic tools for PD. In a PD model

303

induced by α-synuclein oligomers, gene microarray analysis revealed several

304

differentially expressed lncRNAs, including G046036, G030771, AC009365.4,

305

RPS14P3, CTB-11I22.1, and G007549.94 Five of these lncRNAs were subjected to

306

ceRNA analyses, and three lncRNAs among them (AC009365.4, RPS14P3,

307

G046036) showed significant results.94 Another report has revealed that circular

308

alpha-synuclein gene (circSNCA) serve as a ceRNA of miR-7 in PD, and

309

downregulation of circSNCA by pramipexole treatment reduces cell apoptosis and

310

triggers cell autophagy via a mechanism that serves as a miR-7 sponge to upregulate

311

α-syn.95 Heterozygous GBA variants have been frequently related to susceptibility to

312

PD. It has also been reported that the GBAP1 pseudogene acts as a ceRNA for the

313

GBA by sponging miR-22-3p.96 However, reports on ceRNAs in PD-derived

314

exosomes are still have no examples to date.

315 316

4. Exosomes as vehicles for proteins

317

It is believed that exosomes as carriers can disseminate disease pathology for

318

inter-neuronal disease prpagation.30 Protein is another important bioactive molecule

319

dispersed from exosomes to cellular targets over long and short distances. Emerging

320

evidence has shown that many pathogenic forms of proteins have been proven to be

321

associated with exosomes. Amyloid-β peptide (Aβ) and tau in AD,20, 21 α-syn in PD,23

322

prion proteins in scrapie forms27 have been identified to be propagated via exosomes.

323

In particular, for α-syn, previous studies have highlighted that it is more efficient for

324

exosomal α-syn delivered oligomers between cells than free α-syn.24 Many reports

325

confirmed that misfolded α-syn protein propagation between cells can be mediated by 13



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exosomes.24,34,97 Simultaneously, there is evidence that exosomal α-syn protein could

327

be transferred to the adjacent cells in a calcium-dependent manner, resulting in cell

328

death.25 Meanwhile, A recent study elucidates that exosomes are applied to deliver

329

antioxidant protein catalase across the blood-brain barrier (BBB), attenuating

330

neurotoxicity with inflammation in the brain.98 This indicates the potential usefulness

331

of the exosomes on delivering therapeutic proteins. Altogether, the evidence implies

332

the role of proteins associated with PD can be delivered by the exosomes.

333

It should be noted that the majority of extracellular α-syn is found in CSF.99 A

334

fraction of α-syn is present in exosomes with many studies revealing the role of

335

exosomal α-syn in serving as a desired biomarker for diagnosis. Stuendl et al. reported

336

that α-syn in the CSF exosomes could be a potential biomarker to diagnose PD or

337

dementia with a high sensitivity and specificity for identification.23 Shi et al.

338

considered that CNS-derived exosomal α-syn in the plasma can serve as a PD

339

biomarker, via L1 cell adhesion molecule (L1CAM) labeled exosome efflux into the

340

blood.100 It is known that L1CAM is a marker on the surface of exosomes derived

341

from the CNS.

342

The above results indicate that exosomes are proper vehicles for the transmission

343

of PD related proteins and could be potential biomarker for PD diagnosis. Therefore,

344

modification of exosomes to accomplish protein targeted delivery, thus influencing

345

PD progress, could be realizable.

346 347

5. Conclusion and perspectives

348

As an intercellular communication system, exosomes could transport many types

349

of biomolecules, from nucleic acids to proteins. In this review, we highlighted that

350

exosomes exhibit a great potential capability as diagnostic and therapeutic tools for

351

PD. The characteristics of exosomes are: 1) Compared to other nanoparticulated

352

systems, exosomes easily to transport their contents; 2) As a delivery system,

353

exosomes are prone to be present in body fluids during the whole lifespan; 3)

354

Exosomes loaded with drugs can penetrate through the BBB, and the drugs can

355

therefore reach the brain. Before exosomes become transport carriers, further studies 14


Page 15 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


356

are still needed to reveal the molecular machinery regarding the import of proteins,

357

e.g. α-syn, into exosomes. Individualizing and modifying exosomes from the PD

358

patients themselves may turn the modified exosomes into tablet or injection for

359

treatment of patients, so as to slow down the progression of PD and promote neuronal

360

regeneration (Figure 3). However, exosome-associated modifications and clinical

361

treatments may not be an easy task. A series of examinations from basic research and

362

clinical practice should be performed. Therefore, modification with exosomes from

363

parental cells may be a novel treatment strategy for neurodegenerative diseases.

364 365

Figure Legends.

366

Figure 1. Schematic representation of the biogenesis of exosomes. The molecular

367

mechanism for exosome biogenesis could be divided into two types according to (in-)

368

dependence on the Endosomal Sorting Complex Response for Transport (ESCRT).

369

Four distinct ESCRT protein complexes have been identified in the classic

370

ESCRT-dependent pathway, ESCRT-0、ESCRT-Ⅰ、ESCRT-Ⅱ、ESCRT-Ⅲ. Two

371

pathways in MVB generation assist release and trafficking: (1) lysosomal

372

degradation; (2) fusion with the plasma membrane, and release exosomes. Exosomes

373

can be identified by a variety of markers, including tetraspanins CD9, CD63, and

374

CD81. Transmission of toxic proteins, such as abnormal aggregate α-syn, among

375

neurons, microglia and astrocytes are thought to be mediated by exosomes.

376 377

Figure 2. Exosomes as mediators of neuron-glia intercellular communication in

378

PD progression. Exosomes carrying α-syn monomers, oligomers and fibrils released

379

from injured neurons, which then spread to healthy neurons, astrocytes and microglia.

380

Exosomes from glia containing α-syn and inflammatory factors cause the propagation

381

of inflammatory response, which exacerbates neuronal dysfunctions and progression

382

of PD.

383 384

Figure 3. Exosomes as potential biological tools for diagnosis and therapy.

385

Modifying the structure and reducing the exosomal numbers in PD have been 15



Page 16 of 32

386

proposed as a disease therapy strategy. Exosomes can serve as putative biomarkers to

387

monitor PD progression since cargos of exosomes relating with PD are in abundance.

388

Exosomes can also serve as ideal vehicles for delivery of therapeutic drugs and

389

molecules to target sites.

390 391

List of abbreviations:

392

Aβ: Amyloid-β peptide;

393

AD: Alzheimer's disease;

394

α-syn: α-synuclein;

395

BBB: blood-brain barrier;

396

ceRNAs: Competing endogenous RNAs;

397

CNS: central nervous system;

398

circSNCA: circular alpha-synuclein gene;

399

CSF: cerebrospinal fluid;

400

EEs: early endosomes;

401

EVs: extracellular vesicles;

402

GBA: glucocerebrosidase gene;

403

GCase: glucocerebrosidase;

404

ILVs: intraluminal vesicles;

405

LBs: Lewy bodies;

406

LNs: Lewy neuritis;

407

lncRNA: long non-coding RNA;

408

miRNAs: microRNAs;

409

MVB: multivesicular body;

410

PD: Parkinson’s Disease;

411

PM: plasma membrane;

412

siRNAs: small interfering RNAs;

413

TEM: transmission electron microscope.

414 415

Acknowledgements 16


Page 17 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


416

We would like to thank members of the Li lab for their intellectual input. We

417

would also like to thank Dr. Andrew C. McCourt for the language editing. This work

418

was supported by the National Natural Science Foundation (81430025, U1801681),

419

Liaoning Provincial Natural Science Foundation (20180550924), China Postdoctoral

420

Science Foundation (2018M641733) and also by the support of the Swedish Research

421

Council

422

(REfreAME), EU H2020-MSCA-ITN-2016 (Syndegen), BAGADILICO-Excellence

423

in Parkinson and Huntington Research, the Strong Research Environment MultiPark

424

(Multidisciplinary research on Parkinson's disease), the Swedish Parkinson

425

Foundation (Parkinsonfonden), Torsten Söderbergs Foundation, and the Olle Engkvist

426

Byggmästere Foundation.

(K2015-61X-22297-03-4),

EU-JPND

(aSynProtec)

and

EU-JPND

427 428

Conflicts of interest

429

The authors declare no conflict of interest.

430 431

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Figure 1. Schematic representation of the biogenesis of exosomes. The molecular mechanism for exosome biogenesis could be divided into two types according to (in-) dependence on the Endosomal Sorting Complex Response for Transport (ESCRT). Four distinct ESCRT protein complexes have been identified in the classic ESCRT-dependent pathway, ESCRT-0、ESCRT-Ⅰ、ESCRT-Ⅱ、ESCRT-Ⅲ. Two pathways in MVB generation assist release and trafficking: (1) lysosomal degradation; (2) fusion with the plasma membrane, and release exosomes. Exosomes can be identified by a variety of markers, including tetraspanins CD9, CD63, and CD81. Transmission of toxic proteins, such as abnormal aggregate α-syn, among neurons, microglia and astrocytes are thought to be mediated by exosomes.



Figure 2. Exosomes as mediators of neuron-glia intercellular communication in PD progression. Exosomes carrying α-syn monomers, oligomers and fibrils released from injured neurons, which then spread to healthy neurons, astrocytes and microglia. Exosomes from glia containing α-syn and inflammatory factors cause the propagation of inflammatory response, which exacerbates neuronal dysfunctions and progression of PD. 173x126mm (300 x 300 DPI)


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Figure 3. Exosomes as potential biological tools for diagnosis and therapy. Modifying the structure and reducing the exosomal numbers in PD have been proposed as a disease therapy strategy. Exosomes can serve as putative biomarkers to monitor PD progression since cargos of exosomes relating with PD are in abundance. Exosomes can also serve as ideal vehicles for delivery of therapeutic drugs and molecules to target sites. 173x81mm (300 x 300 DPI)




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Exosomes in Parkinson's disease: current perspectives and future

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