Infection with mosquito-borne alphavirus induces selective loss of dopaminergic neurons, neuroinflammation and widespread protein aggregation

Bantle, Collin M.; Phillips, Aaron T.; Smeyne, Richard J.; Rocha, Savannah M.; Olson, Ken E.; Tjalkens, Ronald B.

doi:10.1038/s41531-019-0090-8

Cited by 75 publications

(66 citation statements)

References 84 publications

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“…Another neurotropic virus, the mosquito-borne alphavirus, Western equine encephalitic virus (WEEV) also induces post-encephalitic parkinsonism. Like the influenza virus, WEEV induced activation of microglia and astrocytes, selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and behavioral abnormalities consistent with PD in mouse models 130 . Importantly, the common denominator of these viruses is that they enter the CNS and directly infect cells.…”

Section: Covid-19 and The Possibility Of A Post-viral Parkinsonism: Cmentioning

confidence: 99%

COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

Sulzer

Antonini

Leta

et al. 2020

npj Parkinsons Dis.

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149

165

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This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson's disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and a comparison of healthy and infected brains is important. In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of parkinsonism apart from a single case report. We recommend consensus guidelines for the clinical treatment of Parkinson's patients with COVID-19. While a role for the virus in causing or exacerbating Parkinson's disease appears unlikely at this time, aggravation of specific motor and non-motor symptoms has been reported, and it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia.

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Section: Covid-19 and The Possibility Of A Post-viral Parkinsonism: Cmentioning

confidence: 99%

COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

Sulzer

Antonini

Leta

et al. 2020

npj Parkinsons Dis.

Self Cite

149

165

View full text Add to dashboard Cite

show abstract

“…Given the particular sensitive phenotype of nigrostriatal DA neurons, they might be vulnerable to the release of reactive oxygen species and would be among the first cell populations to be affected. This DA neuron loss may sometimes be paralleled by aggregation of α-syn and may persist even after the infection has ceased [54]. On the other hand, if the disease process is further defined by multiple sequential hits, inhibiting LRRK2 during these events may prove most effective in protecting the already stressed DA neurons.…”

Section: Viewpoint -Is Lrrk2 Inhibition In Parkinson's Patients Suffimentioning

confidence: 99%

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Linstow

Gan‐Or

Brundin

2020

Transl Neurodegener

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Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

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“…aggregation via HEN. This includes microbial surfaces (Bantle et al, 2019;Ezzat et al, 2019), lipid vesicles (Habchi et al, 2018), and nanoparticles (Linse et al, 2007). Additionally, polymer surfaces such as glycosaminoglycans (GAGs) (Iannuzzi et al, 2015) and nucleic acids (Liu and Zhang, 2011) have been shown to accelerate amyloid aggregation.…”

Section: Amyloid Nucleation Mechanismsmentioning

confidence: 99%

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

et al. 2020

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Amyloids are fibrillar protein aggregates associated with diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes and Creutzfeldt-Jakob disease. The process of amyloid polymerization involves three pathological protein transformations; from natively folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow seed-induced (prions) or surface-induced (including microbially induced) HEN pathways. Critically, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions, including replacement therapies.

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Infection with mosquito-borne alphavirus induces selective loss of dopaminergic neurons, neuroinflammation and widespread protein aggregation

Cited by 75 publications

References 84 publications

COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

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