Infectious Agents as Potential Drivers of α‐Synucleinopathies

Abstract

α‐synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α‐synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α‐synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α‐synucleinopathies, (3) pre‐existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society

Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease

“…α-synuclein, like the aforementioned amyloids, can propagate in a prion-like manner ( Holmes and Diamond, 2014 ). Upregulation of α-synuclein in response to an immune activation was recently reviewed in the context of Parkinson’s disease ( Kasen et al, 2022 ; Linard et al, 2022 ).…”

“…Neurodegenerative diseases, including AD, share several common pathologies including alterations to the levels of oligomeric amyloids in the blood and/or CSF ( Klein et al, 2001 ; Tokuda et al, 2010 ; Benilova et al, 2012 ; Pietroboni et al, 2019 ; Majbour et al, 2020 ; Montalbano et al, 2020 ; Singh et al, 2020 ). Studies have shown that several oligomeric amyloids ( Voth et al, 2020 ) including Aβ ( Soscia et al, 2010 ; White et al, 2014 ; Bourgade et al, 2015 ; Kumar et al, 2016 ; Eimer et al, 2018 ), tau ( Kobayashi et al, 2008 ), α-synuclein ( Tulisiak et al, 2019 ; Linard et al, 2022 ), superoxide dismutase-1 ( Pasupuleti et al, 2009 ) and perhaps others, such as TDP-43 ( Bandea, 2013 ), are antimicrobial peptides generated as an innate immune response. These studies and others have encouraged the formation of the antimicrobial protection hypothesis of AD ( Moir et al, 2018 ).…”

Infectious diseases and cognition: do we have to worry?

“…The role that infections play as precipitating and participating factors in neuropathology and neurodegeneration represents a vast field of investigation and a myriad of basicresearch studies are available. However, frequently reported mechanisms that may ultimately induce neuropathology or neurodegeneration, and that various pathogens share, are the induction/interaction of systemic and neurologic inflammation, vascular damage, direct damage (neurotropism), hyperphosphorylation of tau protein, and abnormal aggregation of peptides and proteins such as beta-amyloid, and alphasynuclein [88][89][90][91].…”

Endogenous Alpha-Synuclein is Essential for the Transfer of Pathology by Exosome-Enriched Extracellular Vesicles, Following Inoculation with Preformed Fibrils in vivo

“…Abnormal α-synuclein (α-Syn) deposition and spreading comprise a common denominator in a wide range of neurodegenerative disorders, collectively termed synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) [ 1 , 2 ]. However, up to date, the processes that drive the spread of α-Syn pathology have not been deciphered.…”