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An iPSC-derived neuronal model of DNAJC6 parkinsonism reveals neurodevelopmental and synaptic vesicle recycling defects

ABSTRACT: Biallelic mutations in DNAJC6 cause a complex, early-onset movement 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-specific 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. DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated synaptic vesicle (SV) recycling at the presynaptic terminal. 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 dysregulation of key neurodevelopmental pathways affecting ventral midbrain pattering and neuronal maturation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208353 | GEO | 2023/12/31

REPOSITORIES: GEO

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