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- Title
In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition.
- Authors
Lin, Min; Mackie, Phillip M.; Shaerzadeh, Fatima; Gamble-George, Joyonna; Miller, Douglas R.; Martyniuk, Chris J.; Khoshbouei, Habibeh
- Abstract
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.
- Subjects
DOPAMINE receptors; DOPAMINERGIC neurons; INDUCED pluripotent stem cells; PARKINSON'S disease; DOPAMINE agonists
- Publication
Acta Neuropathologica Communications, 2021, Vol 9, Issue 1, p1
- ISSN
2051-5960
- Publication type
Article
- DOI
10.1186/s40478-021-01203-9