PXD024286

PXD024286 is an original dataset announced via ProteomeXchange.

Title	Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:29:04.557.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jeovanis Gil
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-22 01:44:28	ID requested
1	2022-10-14 00:46:34	announced
⏵ 2	2023-11-14 08:29:08	announced	2023-11-14: Updated project metadata.

Pircs K, Drouin-Ouellet J, Horv, á, th V, Gil J, Rezeli M, Garza R, Grassi DA, Sharma Y, St-Amour I, Harris K, J, ö, nsson ME, Johansson PA, Vuono R, Fazal SV, Stoker T, Hersbach BA, Sharma K, Lagerwall J, Lagerstr, ö, m S, Storm P, H, é, bert SS, Marko-Varga G, Parmar M, Barker RA, Jakobsson J, Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease. Brain, 145(9):3035-3057(2022) [pubmed]

submitter keyword: autophagy, direct neural reprogramming,Huntington disease, CRISPR interference, Proteogenomics, lentiviral vector

Johan Jakobsson
contact affiliation	Dept of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Sweden
contact email	johan.jakobsson@med.lu.se
lab head
Jeovanis Gil
contact affiliation	Lund University
contact email	jeovanis.gil_valdes@med.lu.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024286
     1. Label: PRIDE project
     2. Name: Distinct sub-cellular autophagy impairments occur independently of protein aggregation in aged induced neurons from patients with Huntington’s disease