帕金森病
神经科学
诱导多能干细胞
生物
肌张力障碍
多巴胺能
疾病
医学
基因
遗传学
多巴胺
内科学
胚胎干细胞
作者
Lucia Abela,Lorita Gianfrancesco,Erica Tagliatti,Giada Rossignoli,Katy Barwick,Clara Zourray,Kimberley M. Reid,Dimitri Budinger,Joanne Ng,John R. Counsell,Alec W.M. Simpson,Toni S. Pearson,Simon Edvardson,Orly Elpeleg,Frances M. Brodsky,Gabriele Lignani,Serena Barral,Manju A. Kurian
出处
期刊:Brain
[Oxford University Press]
日期:2024-01-18
标识
DOI:10.1093/brain/awae020
摘要
DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harboring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic (mDA) neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle (SV) recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. In order to explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
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