An Infection Hypothesis of Parkinson’s Disease

Karpenko, Marina N.; Muruzheva, Zamira M.; Pestereva, Nina; Екимова, И. В.

doi:10.1007/s11055-019-00769-1

Cited by 9 publications

(3 citation statements)

References 64 publications

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“…On other hand, the burden of the long-term neurological morbidity from neuroinfectious diseases is largely unknown [13]. A growing body of evidence suggests that the pathological process of PD may be modulated (or initiated) by viruses or other pathogens [20][21][22][23][24][25]. An early evidence of a potential link between viruses and PD stems from an epidemic of Encephalitis Lethargica (EL), following the 1918 influenza outbreak.…”

mentioning

confidence: 99%

COVID-19 and Parkinson’s Disease: Are We Dealing with Short-term Impacts or Something Worse?

Victorino

Guimarães‐Marques

Nejm

et al. 2020

JPD

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We read with great interest the commentary by Helmich and Bloem [1] in which the authors suggested that patients with Parkinson's disease (PD) may not only face a greater risk of developing worse coronavirus disease 2019 (COVID-19)-related respiratory outcomes, but also a variety of "hidden sorrows" of the pandemic. The authors argue that PD patients may suffer from chronic stress and lack of physical activity associated with social isolation. As the COVID-19 continues snaking its way around the world (as of April 29, 2020, global cases topped 3 million), we would like to further highlight several impacts that the ongoing COVID-19 pandemic may induce on the global burden of PD. Preliminary studies suggested that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the etiologic agent of the COVID-19, may have a potential neurotropism in humans though such feature has not been conclusively demonstrated yet [2, 3]. Similar to other respiratory viruses, the SARS-CoV-2 may gain access to the Central Nervous System (CNS) by the hematogenous route or axonal transport along with the olfactory neuroepithelium [4, 5]. The olfactory pathway hypothesis for SARS-CoV-2 neuroinvasion is supported by the fact

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mentioning

confidence: 99%

COVID-19 and Parkinson’s Disease: Are We Dealing with Short-term Impacts or Something Worse?

Victorino

Guimarães‐Marques

Nejm

et al. 2020

JPD

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“…Older age in combination with genetic profile and/or exposure to environmental pollution (herbicides, pesticides, infectious agents, etc.) are considered causative factors of sporadic PD onset and progression [4,5]. PD diagnosis relies on clinically significant symptoms, such as resting tremors, bradykinesia, muscular rigidity, and loss of balance.…”

Section: Introductionmentioning

confidence: 99%

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Pazi,

Belan,

Komarova

et al. 2024

IJMS

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The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson’s disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.

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“…[ 1–3 ] While the exact pathological link between abnormal protein aggregation and microbial infection is still largely unknown. “Amyloid cascade hypothesis” and “microbial infection hypothesis” have driven different prevention and treatment strategies to design i) amyloid inhibitors for preventing amyloid aggregation and ii) antibiotics for preventing microbial infection, [ 4–6 ] most of which do not achieve any clinical success. Due to the multifactorial nature of PMDs, single‐target prevention strategies provide marginal benefits for amyloid inhibition and medical treatments.…”

Section: Introductionmentioning

confidence: 99%

Design and Engineering of Amyloid Aggregation‐Prone Fragments and Their Antimicrobial Conjugates with Multi‐Target Functionality

Zhang

Tang

Liu

et al. 2021

Adv Funct Materials

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Amyloid aggregation and microbial infection are considered major risk factors for neurodegeneration and neuroinflammation in protein misfolding diseases (PMDs), including Alzheimer's disease (AD) and Type 2 diabetes (T2D). However, current amyloid inhibitors are mostly limited to single‐target prevention strategies against specific amyloid proteins or pathogenic microbes, leading to no success for clinical cures of PMDs. Here, a step‐by‐step strategy to design new, multi‐target amyloid aggregation‐prone fragments (APFs) and their APFs antimicrobial agent conjugates is proposed, capable of achieving the stepwise improved multifunctionality of amyloid inhibition, antimicrobial activity, and amyloid imaging. The two APFs of KLVFF from Aβ (associated with AD) and FGAIL from hIAPP (associated with T2D) with β‐structure‐forming property are selected and used as building block to construct a hybrid KLVFFGAIL peptide (K9) and a K9‐AMC (7‐amino‐4‐methylcoumarin) fluorescence conjugate, both of which have demonstrated the improved, multiple‐target, sequence‐independent functions to inhibit the aggregation of both Aβ and hIAPP, reduce both Aβ‐ and hIAPP‐induced cell toxicity, prevent different microbial growth, and introduce fluorescence images for amyloid fibrils. The sequence‐independent amyloid inhibition function of K9 and K9‐AMC mainly stems from their cross‐interactions with amyloid proteins via β‐structure and aromatic interactions. This work provides a proof‐of‐concept example to not only explore a new family of APFs as antimicrobial and anti‐amyloid drugs for the therapeutic potential of PMDs, but also better understand the pathological links between protein aggregation and microbial infection in PMDs along the gut–brain axis.

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An Infection Hypothesis of Parkinson’s Disease

Cited by 9 publications

References 64 publications

COVID-19 and Parkinson’s Disease: Are We Dealing with Short-term Impacts or Something Worse?

COVID-19 and Parkinson’s Disease: Are We Dealing with Short-term Impacts or Something Worse?

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Design and Engineering of Amyloid Aggregation‐Prone Fragments and Their Antimicrobial Conjugates with Multi‐Target Functionality

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