Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

Donnelly, Kirby M; Coleman, Cevannah M.; Fuller, Madison L.; Reed, Victoria L.; Smerina, Dayna; Tomlinson, David S.; Pearce, Margaret M.P.

doi:10.3389/fnins.2022.946822

Cited by 10 publications

(5 citation statements)

References 201 publications

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“…By transplanting iPSC-derived brain cells into the mouse brain, we were able to demonstrate what cellular pathways and networks are altered in young AD patient hippocampal cells and compare them to those present in ADHS grown in vitro and patient post-mortem tissue. Importantly, we showed a putative transfer of cellular pathology from diseased cells to healthy ones, like what has been proposed for other neurodegenerative diseases [68][69][70]. This new human/mouse chimeric model represents a powerful resource to better study the mechanisms underlying the cellular origins and progression of human AD pathogenesis, in vivo.…”

Section: Discussionsupporting

confidence: 71%

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

Pomeshchik

Velásquez

Gil

et al. 2023

Preprint

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The hippocampus is a primary region affected in Alzheimer s disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis in patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of proteomic alterations in AD patient brain cells, associated with increased levels of beta-sheet structures and Ab42 peptides. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of disease progression from early to end stage AD. Our data showcase patient-based models to study the cellular origin, progression, and prion-like spread of AD pathogenesis.

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Section: Discussionsupporting

confidence: 71%

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

Pomeshchik

Velásquez

Gil

et al. 2023

Preprint

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“…HTT knockout is embryonic lethal, while conditional knockout induces progressive neurodegenerative phenotypes in adult mice. This highlights the indispensable role of HTT expression in the normal development of the CNS [336].…”

Section: Other Neurodegenerative Disordersmentioning

confidence: 83%

Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches

Firdaus,

2024

IJMS

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Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs—amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.

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“…“Seeding-competent” mHTT aggregates are defined by their ability to nucleate or “seed” the aggregation of normally-soluble wtHTT proteins, a defining characteristic of infectious prion and other prion-like proteins (Jucker and Walker, 2018; Donnelly et al, 2022). Many studies have pointed to a role for defective clearance by endolysosomal pathways in promoting the propagation of pathogenic aggregates (Freeman et al, 2013; Jiang et al, 2017; Chen et al, 2019; Jiang and Bhaskar, 2020; Polanco and Götz, 2022).…”

Section: Resultsmentioning

confidence: 99%

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Davis,

Zaya,

Panning Pearce

2023

Preprint

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Amyloid aggregate accumulation and spread between synaptically-connected regions of the brain is a hallmark of neurodegenerative disease progression. Glia participate in neuropathogenesis by reducing protein aggregate loads via phagocytosis while simultaneously acting as vectors for aggregate spread between cells. Emerging evidence supports the hypothesis that aggregate accumulation compromises the ability of glia to clear toxic material from the brain, possibly by disrupting the phagolysosomal compartment. A better understanding of how glia become deficient in the disease state could reveal novel therapeutic targets. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade axonal debris in aDrosophilamodel of Huntington’s disease (HD). mHTT aggregate formation in neurons slowed engulfment and clearance of injured axons and caused accumulation of late phagosomes and lysosomes in glia. Neuronal mHTT expression induced innate immunity and phagocytic genes, some of which regulated mHTT aggregate burden in the brain. A forward genetic screen targeting glial Rab GTPases revealed Rab10 as a novel modifier of mHTT aggregate transmission from neurons to glia that acts downstream of the phagocytic receptor, Draper. This suggests that Rab-mediated intercellular vesicle sorting mechanisms could create opportunities for prion-like mHTT aggregates to escape lysosomal degradation. Together, our findings support a model in which mHTT aggregate build-up within the phagolysosomal system impairs glial phagocytosis while also promoting the generation of seeding-competent pathological proteins. The new mechanistic information we report here adds to a growing recognition of phagocytic glia as double-edged players in prion-like proteopathies such as HD.SIGNIFICANCE STATEMENTDeposition of amyloid aggregates is closely associated with neurodegenerative disease progression and neuronal death. Recent studies highlight glia as dynamic mediators of disease, capable of phagocytosing dying neurons and amyloid aggregates, while also inducing chronic inflammation and promoting proteopathic spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in aDrosophilamodel of Huntington’s disease that neuronal mHTT aggregates interfere with glial phagocytic functions, stimulate innate immunity signaling, and impair phagolysosomal processing. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates, suggesting that Rab-mediated intramembrane fusion in the phagolysosomal system could drive aggregate pathology spread.

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Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

Cited by 10 publications

References 201 publications

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

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