BibTex format
@article{Abela:2024:brain/awae020,
author = {Abela, L and Gianfrancesco, L and Tagliatti, E and Rossignoli, G and Barwick, K and Zourray, C and Reid, KM and Budinger, D and Ng, J and Counsell, J and Simpson, A and Pearson, TS and Edvardson, S and Elpeleg, O and Brodsky, FM and Lignani, G and Barral, S and Kurian, MA},
doi = {brain/awae020},
journal = {Brain},
pages = {2023--2037},
title = {Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.},
url = {http://dx.doi.org/10.1093/brain/awae020},
volume = {147},
year = {2024}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - Abela,L
AU - Gianfrancesco,L
AU - Tagliatti,E
AU - Rossignoli,G
AU - Barwick,K
AU - Zourray,C
AU - Reid,KM
AU - Budinger,D
AU - Ng,J
AU - Counsell,J
AU - Simpson,A
AU - Pearson,TS
AU - Edvardson,S
AU - Elpeleg,O
AU - Brodsky,FM
AU - Lignani,G
AU - Barral,S
AU - Kurian,MA
DO - brain/awae020
EP - 2037
PY - 2024///
SP - 2023
TI - Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy.
T2 - Brain
UR - http://dx.doi.org/10.1093/brain/awae020
UR - https://www.ncbi.nlm.nih.gov/pubmed/38242634
VL - 147
ER -