Selective Vulnerability of Layer 5a Corticostriatal Neurons in Huntington's Disease

Pressl, Christina; Mätlik, Kert; Kus, Laura; Darnell, Paul; Luo, Ji‐Dung; Paul, Matthew R.; Weiss, Alison R.; Liguore, William A.; Carroll, Thomas; Da, Davis; McBride, Jodi L.

doi:10.2139/ssrn.4486500

Cited by 3 publications

(3 citation statements)

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“…Mitochondrial dysfunction is an early pathological mechanism in HD, where mHTT disrupts mitochondria releasing mito-RNAs into the cytoplasm. This, in turn, upregulates the innate immune response in the most vulnerable cell type, striatal spiny neurons (4,5,57,58). It is tempting to speculate that mHTT may lead to compromised paraspeckle function, resulting in a reduced ability to cope with mitochondrial stress and potentially leading to cell death in relevant HD tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder with a wide range of motor, cognitive, and psychological symptoms (1,2). HD is caused by expansions of a naturally occurring CAG (cytosine-adenine-guanine) repeat tract (encoding polyglutamine) in the huntingtin (HTT) gene (3) with selective vulnerability of layer 5a corticostriatal neurons (4,5). The HTT gene has 5 to 35 CAG repeats in unaffected individuals, while mutant HTT (mHTT) contains ≥36 CAG repeats (6,7).…”

Section: Introductionmentioning

confidence: 99%

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Huntingtin is an RNA binding protein and participates in NEAT1 -mediated paraspeckles

Yadav,

Harding,

et al. 2024

Sci. Adv.

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Huntingtin protein, mutated in Huntington’s disease, is implicated in nucleic acid–mediated processes, yet the evidence for direct huntingtin–nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA-immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wild-type and mutant huntingtin revealed long noncoding RNA NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington’s disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin colocalized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a huntingtin interactor, demonstrating huntingtin’s involvement in RNA-mediated functions and paraspeckle regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Huntingtin is an RNA binding protein and participates in NEAT1 -mediated paraspeckles

Yadav,

Harding,

et al. 2024

Sci. Adv.

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“…In the more advanced HD3 and HD4, pyramidal cells in Layers III, V and VI of the cerebral cortex also show cell loss (Sotrel, Paskevich et al 1991). More recent studies have revealed that loss of Layer Va pyramidal neurons, identified as corticostriatal cells, can occur in the early stage of HD (Pressl, Mätlik et al 2024) Neuronal intranuclear inclusions (NII) and neuropil inclusions are present in HD brains (DiFiglia, Sapp et al 1997) and are positive for mutant huntingtin (mHTT) and ubiquitin (Ub) (DiFiglia, Sapp et al 1997, Becher, Kotzuk et al 1998, Gutekunst, Li et al 1999, suggesting that there may be a deficiency in the proteolytic machinery responsible for normally clearing these proteins, resulting in their accumulation to form the inclusions. Autophagy is generally the principal mechanism by which cells clear organelles, long-lived proteins and damaged, misfolded, or aggregated proteins that are poor substrates for the ubiquitin-proteasome system (UPS).…”

Section: Introductionmentioning

confidence: 99%

Pathobiology of the autophagy-lysosomal pathway in the Huntington’s disease brain

Berg,

Veeranna,

Rosa

et al. 2024

Preprint

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Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington’s disease (HD). Although lowering mHTT by stimulating autophagy has been considered a possible therapeutic strategy, the role and competence of autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown. Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex of HD brains staged from HD2 to HD4 by Vonsattel neuropathological criteria compared to controls. Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins p62/SQSTM1 and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. Importantly, no blockage in autophagosome formation and autophagosome-lysosome fusion was detected, thus pinpointing autophagy substrate clearance deficits as a basis for autophagic flux declines. The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but failure at advanced stages contributes to progressive HTT build-up and potential neurotoxicity. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, may have therapeutic benefits in HD patients.

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mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

Stavrides,

Goulbourne,

Peddy

et al. 2024

Preprint

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Huntington’s disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an earlier clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL (Thy-1-RFP-GFP-LC3) to investigatein vivoneuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited high level colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder that included a lowered phospho-p70S6K level, lysosome depletion and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62- and ubiquitin-immunoreactivities, suggesting beneficial potential of autophagy modulation at early stages of disease progression.

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Selective Vulnerability of Layer 5a Corticostriatal Neurons in Huntington's Disease

Cited by 3 publications

References 0 publications

Huntingtin is an RNA binding protein and participates in NEAT1 -mediated paraspeckles

Huntingtin is an RNA binding protein and participates in NEAT1 -mediated paraspeckles

Pathobiology of the autophagy-lysosomal pathway in the Huntington’s disease brain

mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance

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