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The Era of Neurodegenerative Metastasis Mahesh Narayan*
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Department of Chemistry and Biochemistry, The University of Texas at El Paso, El Paso, Texas 79968, United States ABSTRACT: The incidence of converging end points across neurodegenerative disorders, leading to comorbidity, has spurred the search for common neurometabolic denominators among otherwise distinct pathologies. While recent data have hinted at crossover factors, and genetic risk-factors across the neurodegenerative landscape, we discuss the potential of prion-like amyloid proteins as suspects, if not causals, in seeding cross-pathology. While much work remains to be done on how they spread and “fertilize” seemingly unrelated neuropathies, it is safe to assume that the era of neurodegenerative metastasis is here. KEYWORDS: Neurodegeneration, amyloid, oligomers, protofibrils, crossover factors, comorbidity, neurodegenerative metastasis
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by neighboring neurons, and seed-templated misfolding of corresponding soluble amyloids in the recipient neuron. An example by which a seed propagates is via neuronal networks. Such networks include the vagus nerve tract to the medulla, pons, midbrain, cerebellum, and thalamus. Other studies have determined that amyloid seeds released into the extracellular space (synaptic junction) may be internalized by cells in the immediate neighborhood via exosomes or tunneling nanotubes. The latter are membranous in nature and resemble traditional nanotubes with the carbon framework being replaced by polymeric actin. By example, in concert with the progress of Alzheimer’s tau-tangles first observed in the transentorhinal and entorhinal regions permeate into the limbic allocortex and adjoining neocortex. By contrast PDassociated α-synuclein pathology is first detected in dorsal motor nucleus in medulla and anterior olfactory nucleus. As the PD progresses the synucleinopathy invades the amygdala, cholinergic nuclei of the basal forebrain and SnpC. The same biomarker is observed to access the frontal and parietal lobes in DLB, via the temporal lobe. While amyloid seed-spread initially results in the corruption of identical or similar proteins and peptides to evoke pathogenicity at locations proximal to, and even relatively distant from, the original locus, eventually the seeds are disseminated into regions of the brain that are not necessarily related in function. Such neuronal domains are unlikely to natively express the invading amyloid seed. More importantly, they may endogenously express soluble amyloids differing in identity from the invading amyloid. It is then natural to inquire whether an amyloid seed can corrupt the cellular milieu in unrelated host neurons and initiate cross-pathology? And if so, what are neurometabolic trajectories adopted to culminate in cross-toxicity? The notion of cross-toxicity is not new as there is already in vitro evidence for amyloid heterotoxicity.4 Fibrils and oligomers of Aβ[1−42], Aβ[1−40], and α-synuclein, functioning as “seeds”, are known to promote each other’s aggregation pathways. Aβ deposits and hyperphosphorylated tau, the
he past few years have seen a renaissance in attempts to comprehend intricacies and nuances within the amyloidome that drive neurodegenerative disorders. The landmark finding that prion-like behavior, once exclusive to the prion protein, is a hallmark of other proteins including amyloid beta (Aβ), tau, α-synuclein, and mutant huntingtin protein (mHTT) spurred efforts to underscore its implications for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB), etc.1 The trait whereby these proteins can form seeds that act as templates for recruiting their soluble counterparts remained the underpinning of many early studies designed to understand the molecular basis of neurotoxicity in their respective degenerative pathologies. Initial focus had been centered on defining the process by which soluble amyloids convert to their fibrillary or plaque counterparts. However, it has been established for some time now that plaque and fibril load does not dictate disease burden. The paradigm-shifting conclusion, found to be broadly applicable across heterogeneous amyloids and distinct neurodegenerative disease-types, drove attention to other constituents populating the soluble-amyloid to insoluble-fibril trajectory. It was then discovered that soluble oligomers and smaller aggregates known as protofibrils, both of which are onpathway to mature fibril formation, are associated with the onset and propagation of their associated pathologies.2 It is these oligomers and protofibrils that are the so-called “seeds” in neurodegenerative pathologies because, as previously stated, they serve to template soluble amyloid monomers into altered, toxic conformations. The pathogenic seeds of amyloidogenic proteins have been known to “spread”.3 That is, they infiltrate into other cells and “transmit” their respective (seed-specific) pathologies. This spreading behavior correlates with the progress of the disease [Scheme 1A]. Though the specifics involving intercellular transfer of amyloid conformers remain elusive, and/or poorly understood, a number of possible mechanisms by which amyloid seeds spread from their site of origin have been postulated. The general steps by which interneuronal seed transfer takes places is via seed (oligomers and protofibrils) formation, seed emission from the corrupted neuron, its intake © XXXX American Chemical Society
Received: July 1, 2019 Accepted: July 3, 2019
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DOI: 10.1021/acschemneuro.9b00371 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience Scheme 1a
However, the gene encoding tau, MAPT, has also been linked to frontotemporal dementia (FTD) and progressive supranuclear palsy and more recently to PD [Scheme 1B]. These findings perhaps explain the incidence of comorbidity seen in patients wherein one neurodegenerative pathology creates susceptibility for another. It therefore behooves us to define the molecular roadmap that drives cross-pathology; an area that is not sufficiently resolved.5 In this context, transgenic animal models designed to explore heterotoxic pathways fall short. The shortcomings include poor control over seed infiltration into the location of interest, undefined “time zero” of heterotypic infiltration, incidence of confounding pathologies (homotoxicity is likely to precede, and therefore co-occur with, heterotoxicity), and lack of control pertaining to seed “dose” and seed type (monomer, oligomer, vs protofibril, etc). These lacunae call for alternate models to explore amyloidogenic heterotoxicity including the stereotaxic infusion of amyloid seeds into neuronal domains that do not endogenously express the said seed. Such a metastasis model can directly report on any cross-toxic outcomes elicited by the metastasizing seed. It overcomes confounding variables that are likely to be present when the seed of interest is initially expressed in its native neuron and elicits the pathology affiliated with it, prior to any metastatic impact it may have. Nevertheless, it is perhaps in the light of such emerging, and at times conflicting, data that the NIH has correctly recognized the historical backdrop involving mostly silo-istic research efforts in this arena and called for a more integrated approach to tackling the spectrum of neurodegenerative diseases: “Etiologic and therapeutic research on dementia has focused on either individual disease syndromes (e.g., Alzheimer’s disease, AD; Lewy Body Dementia, LBD, Frontotemporal Dementia, FTD; or Vascular Dementia, VD) or distinct neurodegenerative processes (e.g., Aβ, HPF-Tau, α-syn, TDP-43, small vessel disease). Aside f rom descriptive, post-mortem neuropathology, different neurodegenerative diseases have generally been investigated in isolation f rom one another. There are few models for studying whether and how neurodegenerative disease processes relate to one another. We need to understand how dif ferent neurodegenerative processes interact clinically and physiologically. We need to be able to more precisely identif y which neurodegenerative process or processes are active in individual patients. At the same time, we need to better understand how dif ferent neurodegenerative diseases resemble and dif fer f rom one another at the molecular, cellular, and organismic levels.” (RFA: https://grants.nih.gov/grants/guide/pa-files/ PAS-17-028.html). Needless to say, the era of neurodegenerative mestastasis is here; and here to stay. And unlike cancer where tissues can be biopsied periodically, the limits associated with invading our brains poses interesting challenges that need to be overcome.
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(A) Diagram showing the spread of amyloid proteins through different brain regions as a function of amyloid and disease types. [From: Weickenmeier, J., Kuhl, E., and Goriely, A. (2018) Multiphysics of Prionlike Diseases: Progression and Atrophy. Phys. Rev. Lett. 121, 158101, DOI: 10.1103/PhysRevLett.121.158101]. (B) Overlap in protein pathology in distinct Neurodegenerative disorders. The image shows a Venn diagram to reflect the overlap between key proteins and the diseases with which they are associated. [From: Mathis, C. A., et al. (2017) Small-molecule PET Tracers for imaging Proteinopathies. Semin. Nucl. Med. 47, 553−575, DOI: 10.1053/ j.semnuclmed.2017.06.003].
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hallmark features of AD, have been identified in T2D subjects. Furthermore, the presence of α-synuclein aggregates has been observed in approximately 50% of AD patients. Genome-wide association studies report shared underpinnings between sets of neurodegenerative diseases. These include discovery of the presence of coincidental genetic denominators that have been reported for risk-factors and age-at-onset modifiers. For example, APOE status which is a strong risk-factor and modifier of onset age for AD has been found to associate with PD. Tau-associated pathology is considered a hallmark of AD.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Mailing address: Dept. of Chemistry and Biochemistry, UT El Paso, 500 W. Univ. Ave., El Paso, TX 79968. Phone: 915-747-6614. Fax: 915-7475748. ORCID
Mahesh Narayan: 0000-0002-2194-5228 Notes
The author declares no competing financial interest. B
DOI: 10.1021/acschemneuro.9b00371 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
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ACKNOWLEDGMENTS M.N. acknowledges support from NIH 1SC3 GM111200 01A1, the UTEP College of Science (Research Enhancement Award), Mrs. Holly and Dr. Eddie Vazquez (The El Paso Pain Center) and the NIH MBRS SCORE Border Biomedical Research Center at The University of Texas at El Paso. This facility is supported by Grant # 2G12MD007592 and Grant # 5G12MD007592 from the Research Centers in Minority Institutions program of the National Institutes on Minority Health and Health Disparities, a component of the Research Center in Minority Institutions (RCMI) program.
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REFERENCES
(1) Zhang, Z., Nie, S., and Chen, L. (2018) Targeting prion-like protein spreading in neurodegenerative diseases. Neural Regener. Res. 13, 1875−1878. (2) Cline, E. N., Bicca, M. A., Viola, K. L., and Klein, W. L. (2018) The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J. Alzheimer's Dis. 64, S567−S610. (3) Walker, L. C., Diamond, M. I., Duff, K. E., and Hyman, B. T. (2013) Mechanisms of protein seeding in neurodegenerative diseases. JAMA neurology 70, 304−310. (4) Owen, M. C., Gnutt, D., Gao, M., Wärmländer, S. K. T. S., Jarvet, J., Gräslund, A., Winter, R., Ebbinghaus, S., and Strodel, B. (2019) Effects of in vivo conditions on amyloid aggregation. Chem. Soc. Rev., DOI: 10.1039/C8CS00034D. (5) Kabiraj, P., Marin, J. E., Varela-Ramirez, A., and Narayan, M. (2016) An 11-mer Amyloid Beta Peptide Fragment Provokes Chemical Mutations and Parkinsonian Biomarker sAggregation in Dopaminergic Cells: A Novel Road Map for “Transfected” Parkinson’s. ACS Chem. Neurosci. 7, 1519−1530.
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DOI: 10.1021/acschemneuro.9b00371 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
