Postmortem neuropathology in early Huntington disease

Hedreen, John C; Berretta, Sabina; White III, Charles L

doi:10.1093/jnen/nlae022

Cited by 5 publications

References 55 publications

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Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation

Zimmermann,

Mengel,

Raupach

et al. 2024

J Neurol

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Introduction While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington’s disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions. Methods Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier. Results One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03–0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed—in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions—HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration. Conclusions Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which—given the low repeat number—is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.

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Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation

Zimmermann,

Mengel,

Raupach

et al. 2024

J Neurol

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Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits

Lazaridis,

Crittenden,

Ahn

et al. 2024

Current Biology

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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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Postmortem neuropathology in early Huntington disease

Cited by 5 publications

References 55 publications

Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation

Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation

Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits

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

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