Impaired Oligodendrocyte Maturation Is an Early Feature in SCA3 Disease Pathogenesis DOI Creative Commons
Kristen H. Schuster,

Annie J. Zalon,

Hongjiu Zhang

и другие.

Journal of Neuroscience, Год журнала: 2022, Номер 42(8), С. 1604 - 1617

Опубликована: Янв. 18, 2022

Spinocerebellar ataxia Type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in ATXN3 gene results expression of mutant form protein, deubiquitinase that causes selective neurodegeneration despite being widely expressed. mechanisms driving SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human ATXN3, we identified early robust transcriptional changes selectively vulnerable brain regions implicate oligodendrocytes pathogenesis. We mapped across early, mid, late stages two regions: cerebellum brainstem. significant disease-associated module through weighted coexpression network analysis revealed dysfunction oligodendrocyte maturation. These reflect toxic gain-of-function mechanism, as KO do not exhibit any impairments Genetic crosses reporter marked reduction mature SCA3-disease regions, ultrastructural microscopy confirmed abnormalities axonal myelination. Further study isolated precursor cells from established this impairment maturation cell-autonomous process. conclude simply neurons, search therapeutic strategies biomarkers will need account non-neuronal involvement pathogenesis.SIGNIFICANCE STATEMENT Despite advances spinocerebellar (SCA3) understanding, much remains unknown about how ultimately leading cell death. completed longitudinal transcriptomic define earliest progression. Through analyses followed up with biochemical histologic studies mice, provide evidence severe Our advance understanding mechanisms, identify additional routes intervention, may broader insight into diseases beyond SCA3.

Язык: Английский

Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

и другие.

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

Процитировано

781
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset DOI Creative Commons
Jong‐Min Lee, Kevin Correia, Jacob M. Loupe

и другие.

Cell, Год журнала: 2019, Номер 178(4), С. 887 - 900.e14

Опубликована: Авг. 1, 2019

Язык: Английский

Процитировано

433
The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum DOI Open Access
G Elif Karagöz, Diego Acosta‐Alvear, Peter Walter

и другие.

Cold Spring Harbor Perspectives in Biology, Год журнала: 2019, Номер 11(9), С. a033886 - a033886

Опубликована: Янв. 22, 2019

Most of the secreted and plasma membrane proteins are synthesized on membrane-bound ribosomes endoplasmic reticulum (ER). They require engagement ER-resident chaperones foldases that assist in their folding maturation. Since protein homeostasis ER is crucial for cellular function, protein-folding status organelle's lumen continually surveyed by a network signaling pathways, collectively called unfolded response (UPR). Protein-folding imbalances, or "ER stress," detected highly conserved sensors adjust ER's capacity according to physiological needs cell. We review recent developments field have provided new insights into stress-sensing mechanisms used UPR which they integrate various inputs organelle accommodate fluctuations demands.

Язык: Английский

Процитировано

263
Molecular mechanisms underlying nucleotide repeat expansion disorders DOI
Indranil Malik, Chase P. Kelley, Eric T. Wang

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(9), С. 589 - 607

Опубликована: Июнь 17, 2021

Язык: Английский

Процитировано

258
Tau strains shape disease DOI Creative Commons
Jaime Vaquer‐Alicea, Marc I. Diamond, Łukasz A. Joachimiak

и другие.

Acta Neuropathologica, Год журнала: 2021, Номер 142(1), С. 57 - 71

Опубликована: Апрель 8, 2021

Abstract Tauopathies consist of over 25 different neurodegenerative diseases that include argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s (PiD). are defined by brain accumulation microtubule-associated protein tau in fibrillar aggregates, whose prevalence strongly correlates with dementia. Dominant mutations cause diseases, most increase its aggregation propensity. Pathogenesis tauopathies may involve pathological conformers serve as templates to recruit native into growing assemblies also move between cells progression, similar prions. Prions adopt conformations, termed “strains,” stably propagate living systems, create unique patterns neuropathology. Data from multiple laboratories now suggest acts a prion. It propagates strains indefinitely cultured cells, when these inoculated mouse models, they neuropathological patterns, which establish direct link conformation disease. In humans, distinct fibril structures associated but causality has not been established mice. Cryo-EM fibrils isolated tauopathy brains reveal cores across Interestingly, the monomer unit within subtypes same patient appears relatively preserved. This is consistent data samples an ensemble conformations act pathologic formation restricted numbers strains. The propensity be linked local motifs expose amyloidogenic amino acid sequences. prion hypothesis, predicts structure dictates resultant disease, proved particularly useful understand diversity human tauopathies. challenge develop methods rapidly classify patients according underlying achieve more accurate diagnosis effective therapy.

Язык: Английский

Процитировано

114
From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research DOI Open Access
Andrew Jiang, Renée R. Handley, Klaus Lehnert

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(16), С. 13021 - 13021

Опубликована: Авг. 21, 2023

Huntington’s disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as highly penetrant dominant likely acting through toxic gain of function mutant protein. Widespread cellular degeneration medium spiny neurons caudate nucleus and putamen are responsible for onset symptomology that encompasses motor, cognitive, behavioural abnormalities. Over past 150 years research since George Huntington published his description, plethora pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption proteostasis, transcriptional dysregulation, neuroinflammation. Despite identification characterisation causative gene mutation significant advances our understanding pathology recent years, disease-modifying intervention has not yet clinically approved. This review includes overview disease, from its aetiology to clinical presentation manifestation. An updated view molecular latest therapeutic developments will also be discussed.

Язык: Английский

Процитировано

53
Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease DOI
Sen Yan, Xiaoming Zheng,

Yingqi Lin

и другие.

Nature Biomedical Engineering, Год журнала: 2023, Номер 7(5), С. 629 - 646

Опубликована: Фев. 16, 2023

Язык: Английский

Процитировано

42
Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases DOI
Maria Inês Teixeira, Carla M. Lopes, Maria Helena Amaral

и другие.

European Journal of Pharmaceutics and Biopharmaceutics, Год журнала: 2020, Номер 149, С. 192 - 217

Опубликована: Янв. 23, 2020

Язык: Английский

Процитировано

97
The protective role of exercise against age-related neurodegeneration DOI
Alyson Sujkowski,

Luke Hong,

Robert Wessells

и другие.

Ageing Research Reviews, Год журнала: 2021, Номер 74, С. 101543 - 101543

Опубликована: Дек. 17, 2021

Язык: Английский

Процитировано

90
Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases DOI Creative Commons
Jessica Tittelmeier, Eliana Nachman, Carmen Nussbaum‐Krammer

и другие.

Frontiers in Aging Neuroscience, Год журнала: 2020, Номер 12

Опубликована: Окт. 6, 2020

Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's Huntington's and amyotrophic lateral sclerosis. Pathological inclusions the associated toxicity appear to spread through nervous system characteristic pattern during course disease. This has been attributed prion-like behavior amyloid-type aggregates, which involves self-replication pathological conformation, intercellular transfer, subsequent seeding native forms same protein neighboring cell. Molecular chaperones play major role maintaining cellular proteostasis by assisting (re)-folding ensure their function or promoting degradation terminally prevent damage. With increasing age, however, capacity this network tends decrease, enables manifestation diseases. Recently, there plethora studies investigating how when interact with disease-related proteins, have advanced our understanding misfolding review focuses on steps propagation from initial self-templated replication spreading discusses influence that these various steps, highlighting both positive adverse consequences chaperone action can have. Understanding alleviate aggravate disease progression vital for development therapeutic strategies combat debilitating

Язык: Английский

Процитировано

78