論文 - 詳細
| RRC ID | 69036 |
|---|---|
| 著者 | 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. |
| タイトル | Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease. |
| ジャーナル | Brain |
| Abstract |
Huntington's disease (HD) 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 aging humans. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised 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 ctrl-iNs, 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 rational for future development of autophagy activation therapies. |
| 巻・号 | 145(9) |
| ページ | 3035-3057 |
| 公開日 | 2022-9-14 |
| DOI | 10.1093/brain/awab473 |
| PII | 6479694 |
| PMID | 34936701 |
| PMC | PMC9473361 |
| MeSH | Adult Autophagy / physiology Humans Huntingtin Protein / genetics Huntington Disease* / genetics Neurodegenerative Diseases* Neurons |
| IF | 11.337 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 123 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 606A1(HPS0328) |