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- Title
Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.
- Authors
Abela, Lucia; Gianfrancesco, Lorita; Tagliatti, Erica; Rossignoli, Giada; Barwick, Katy; Zourray, Clara; Reid, Kimberley M; Budinger, Dimitri; Ng, Joanne; Counsell, John; Simpson, Arlo; Pearson, Toni S; Edvardson, Simon; Elpeleg, Orly; Brodsky, Frances M; Lignani, Gabriele; Barral, Serena; Kurian, Manju A
- Abstract
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 harbouring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic 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 recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. 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.
- Subjects
MOVEMENT disorders; GENE therapy; INDUCED pluripotent stem cells; NEURAL development; PARKINSONIAN disorders; SYNAPTIC vesicles
- Publication
Brain: A Journal of Neurology, 2024, Vol 147, Issue 6, p2023
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/awae020