Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy

• Published in: Brain (London, England : 1878) Vol. 147; no. 6; pp. 2023 - 2037
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 03-06-2024
• Subjects: Auxilins - genetics; Auxilins - metabolism; Child; Dopaminergic Neurons - metabolism; Endocytosis - genetics; Endocytosis - physiology; Female; Genetic Therapy - methods; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humans; Induced Pluripotent Stem Cells - metabolism; Male; Mutation; Original; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - therapy; Synapses - genetics; Synapses - metabolism; gene therapy; CME; auxilin; parkinsonism; DNAJC6; neurodevelopmental
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awae020

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.