Back to the future: lessons from past viral infections and the link with Parkinson’s disease

Dowd, Eilís; McKernan, Declan P.

doi:10.1042/ns20200051

Cited by 4 publications

(2 citation statements)

References 85 publications

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“…The large and increasing number of people with post-COVID neurological symptoms has renewed the interest in the link between viruses and neurodegenerative brain disorders. There have been similar findings with other post-viral syndromes, including herpes simplex virus 1 (HSV-1) and its link to Alzheimer's disease (AD) (5) and likewise for influenza virus and Parkinson's disease (PD) (6). More recently, a strong link has been found between Epstein-Barr virus and multiple sclerosis (7).…”

Section: Introductionmentioning

confidence: 66%

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF

Christ

Kapell

Mermelekas

et al. 2022

Preprint

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The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed the interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogenous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as: APLP1 (amyloid beta precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF, and thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 66%

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF

Christ

Kapell

Mermelekas

et al. 2022

Preprint

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“…As cell-cell fusion is a major trigger of cellular senescence, viruses may have developed the ability to exploit host fusogens, promoting premature aging ( Gal et al., 2019 ). Indeed, epidemiological and research data have associated neurotropic viruses with accelerated brain aging and neurodegenerative disorders ( Mavrikaki et al., 2021 ; Sait et al., 2021 ; Filgueira et al., 2021 ; Dowd and McKernan, 2021 ). Along these lines, herpes simplex virus 1 (HSV-1) and human herpesvirus 6 (HHV-6) have been associated with Alzheimer’s disease (AD) and multiple sclerosis (MS) respectively, while human immunodeficiency virus type 1 (HIV-1) contributes to HIV-associated neurocognitive disorders (HAND, 18-19).…”

Section: Introductionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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