Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease.

Pircs K, Drouin-Ouellet J, Horváth V, Gil J, Rezeli M, Garza R, Grassi DA, Sharma Y, St-Amour I, Harris K, Jönsson ME, Johansson PA, Vuono R, Fazal SV, Stoker T, Hersbach BA, Sharma K, Lagerwall J, Lagerström S, Storm P, Hébert SS, Marko-Varga G, Parmar M, Barker RA, Jakobsson J

Brain 145 (9) 3035-3057 [2022-09-14; online 2021-12-23]

Huntington's disease is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in ageing humans. To address this, we generated induced neurons through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. Huntington's disease induced neurons (HD-iNs) displayed profound deficits in autophagy, characterized by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in control induced neurons, highlighting the importance of wild-type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rationale for future development of autophagy activation therapies.

Clinical Genomics Lund [Service]

PubMed 34936701

DOI 10.1093/brain/awab473

Crossref 10.1093/brain/awab473

pii: 6479694
pmc: PMC9473361