In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition

Acta Neuropathologica Communications

Habibeh Khoshbouei¹  Douglas R. Miller¹  Phillip M. Mackie¹  Fatima Shaerzadeh¹  Joyonna Gamble-George¹  Min Lin¹  Chris J. Martyniuk² 

[1] Department of Neuroscience, University of Florida, 32611, Gainesville, FL, USA;Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, 32611, Gainesville, FL, USA;

关键词: α-synuclein;    iPSCs;    Dopamine neurons;    D2 receptor;    Parkinson’s disease;   

DOI  :  10.1186/s40478-021-01203-9

来源: Springer

【 摘 要 】

Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contributes to dopaminergic neuron vulnerability remain unknown. The inaccessibility to diseased tissue has been a limitation in studying progression of pathophysiology prior to degeneration of dopamine neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from a PD patient carrying the α-synuclein triplication mutation (AST) and an unaffected first-degree relative (NAS) into dopaminergic neurons. In human-like dopamine neurons α-synuclein overexpression reduced the functional availability of D2 receptors, resulting in a stark dysregulation in firing activity, dopamine release, and neuronal morphology. We back-translated these findings into primary mouse neurons overexpressing α-synuclein and found a similar phenotype, supporting the causal role for α-synuclein. Importantly, application of D2 receptor agonist, quinpirole, restored the altered firing activity of AST-derived dopaminergic neurons to normal levels. These results provide novel insights into the pre-degenerative pathophysiological neuro-phenotype induced by α-synuclein overexpression and introduce a potential mechanism for the long-established clinical efficacy of D2 receptor agonists in the treatment of PD.

【 授权许可】

CC BY