GSE208353
An iPSC-derived neuronal model of DNAJC6 parkinsonism reveals neurodevelopmental and synaptic vesicle recycling defects
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. Overall design: An aged-matched healty Control, 3 DNAJC6-related parkinsonism patients and one isogenic control (from Patient 2) iPSCs-derived midbrain dopaminergic neurons (3 biological replicates each)