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Distinct sub-cellular autophagy impairments independent of protein aggregation in induced neurons from patients with Huntington disease

ABSTRACT: Distinct sub-cellular autophagy impairments independent of protein aggregation in induced neurons from patients with Huntington disease

PROVIDER: PRJNA758255 | ENA |

REPOSITORIES: ENA

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Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

Project description:Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

| PRJNA703003 | ENA

Distinct sub-cellular autophagy impairments independent of protein aggregation in induced neurons from patients with Huntington disease

Project description:Huntington’s disease(HD)is a hereditary neurodegenerative disorder that is caused by CAGexpansionsin the huntingtin(HTT)gene. Modelling HD in the lab has proven challenging asrodent models poorly reproduce the disease process and cellular models fail to include age-dependent processescrucial tothe disease. Here we generatedinduced neurons(iNs)throughdirect reprogrammingof fibroblastfrombothHD-patients and healthy controls. This procedureresultedin the generation ofpatient-derived HD neurons that retainedage-dependentcharacteristics. We found that HD-iNsconsistentlydisplayedshorterandfewerneuritescomparted to ctrl-iNsandthat thisphenotypecould be rescuedbyCRISPRi-mediated silencingof mHTT.Proteomics analysis demonstrated an alteration in AMPK-signalling and autophagyin HD-iNs. In line with this,HD-iNs displayeda distinctalteration inautophagy activity,characterizedby areduction in thetransportoflate autophagic structuresfrom neurites tothecell-bodyand subsequent cargo degradation.These results identify a novel therapeutic targetfor HD and provides a rational for futuredevelopmentof CRISPR-based approaches to treatHD

2022-07-22 | GSE182866 | GEO

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the disease. Here we generated induced neurons (iNs) that retained age-dependent epigenetic characteristics of the donors through direct reprogramming of skin fibroblasts. HD-iNs displayed a transcriptionally regulated, distinct neurite specific alteration in autophagy, characterized by reduced transport of late autophagic structures and subsequent cargo degradation. In addition, HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of both HTT alleles did not rescue the morphology nor the autophagic defect in HD-iNs. Strikingly, it resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wt HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt HTT in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific HTT silencing approaches, some of which are now in clinical trials.

2022-02-01 | GSE167104 | GEO

Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation

Project description:Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates resulting in alterations in autophagy. However, the consequences of impaired autophagy on neuronal function remain poorly understood. In this study, we used cell culture and mouse models of huntingtin protein aggregation, as well as post-mortem material from patients with Huntington's disease to demonstrate that Argonaute-2 (AGO2) accumulates in the presence of neuronal protein aggregates and that this is due to impaired autophagy. Accumulation of AGO2, a key factor of the RNAinduced silencing complex that executes microRNA functions, results in global alterations of microRNA levels and activity. Together these results demonstrate that impaired autophagy found in neurodegenerative diseases not only influences protein aggregation, but also directly contributes to global alterations of intracellular posttranscriptional networks.

2018-08-07 | GSE78928 | GEO

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease

Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the expression of the disease clinically. Here we generated induced neurons (iNs) through direct reprogramming of skin fibroblasts from HD-patients. This resulted in the generation of patient-derived HD neurons that retained age-dependent epigentic characteristics of the donors. Using these cells, we then undertook a proteomic analysis and demonstrated there was an alteration in the CAMKK-AMPK pathway and autophagy in these HD-iNs, compared to healthy control iN cells. In line with this, HD-iNs displayed a distinct subcellular alteration in autophagy, specifically in the neurites, characterized by a reduction in the transport of late autophagic structures between neurites and the soma and subsequent cargo degradation. In addition to which the HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of HTT (both wt and mutant) did not rescue the morphology nor could this rescue the autophagic defect in HD-iNs and indeed resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt Htt in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific htt silencing approaches, some of which are now in clinical trials.

2022-10-14 | PXD024286 | Pride

Autophagy impairments in directly reprogrammed neurons in patients with idiopathic Parkinson’s disease

Project description:Autophagy impairments in directly reprogrammed neurons in patients with idiopathic Parkinson’s disease

| PRJNA515626 | ENA

Expression data from human Huntington fibroblasts

2013-03-28 | GSE45516 | GEO

Expression data from human Huntington fibroblasts

Project description:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients Comparison between six Huntington human fibroblasts and three normal controls. All individuals were aged and sex matched. In fact they are all males with the subsequent ages: 28, 48, 57 for the controls and 38, 63, 57, 47, 38, 37 for the HD patients. The average age is comparable.

2013-03-28 | E-GEOD-45516 | biostudies-arrayexpress

Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation

Project description:Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation

| PRJNA314448 | ENA

RARb and Huntington Disease

Project description:RARb and Huntington Disease

| PRJNA1129147 | ENA