Dataset Information

Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.

ABSTRACT: Mutant huntingtin, which causes Huntington's disease (HD), is ubiquitously expressed but induces preferential loss of striatal neurons by unclear mechanisms. Rab11 dysfunction mediates homeostatic disturbance of HD neurons. Here, we report that Rab11 dysfunction also underscores the striatal vulnerability in HD. We profiled the proteome of Rab11-positive endosomes of HD-vulnerable striatal cells to look for protein(s) linking Rab11 dysfunction to striatal vulnerability in HD and found XK, which triggers the selective death of striatal neurons in McLeod syndrome. XK was trafficked together with Rab11 and was diminished on the surface of immortalized HD striatal cells and striatal neurons in HD mouse brains. We found that XK participated in transporting manganese, an essential trace metal depleted in HD brains. Introducing dominantly active Rab11 into HD striatal cells improved XK dynamics and increased manganese accumulation in an XK-dependent manner. Our study suggests that impaired Rab11-based recycling of XK onto cell surfaces for importing manganese is a driver of striatal dysfunction in Huntington's disease.

SUBMITTER: Chhetri G

PROVIDER: S-EPMC9475296 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.

Chhetri Gaurav G Ke Yuting Y Wang Ping P Usman Muhammad M Li Yan Y Sapp Ellen E Wang Jing J Ghosh Arabinda A Islam Md Ariful MA Wang Xiaolong X Boudi Adel A DiFiglia Marian M Li Xueyi X

The Journal of cell biology 20220913 10

Mutant huntingtin, which causes Huntington's disease (HD), is ubiquitously expressed but induces preferential loss of striatal neurons by unclear mechanisms. Rab11 dysfunction mediates homeostatic disturbance of HD neurons. Here, we report that Rab11 dysfunction also underscores the striatal vulnerability in HD. We profiled the proteome of Rab11-positive endosomes of HD-vulnerable striatal cells to look for protein(s) linking Rab11 dysfunction to striatal vulnerability in HD and found XK, which ...[more]

PMID: 36099524

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Project description:The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease. However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to use a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with Huntington's disease pathology, we hypothesized that a general hypersensitivity to costs would underpin Huntington's disease apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease, n = 53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with Huntington's disease accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and drift rate, where there was moderate evidence of Huntington's disease apathy drifting faster towards the immediately available (low-cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in Huntington's disease, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that Huntington's disease pathology may cause a domain-general disruption of cost processing, which is distinct from apathy occurrence in other brain disorders and may require different therapeutic approaches.

Dataset Information

Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.

Publications

Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.

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