The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease

Our understanding of the molecular mechanisms underlying differential vulnerability of substantia nigra dopamine neurons in Parkinson's disease (PD) remains limited, and previous therapeutic efforts targeting rodent nigral neurons have not been successfully translated to humans. However, recent emergence of induced pluripotent stem cell technology has highlighted some fundamental differences between human and rodent midbrain dopamine neurons that may at least in part explain relative resistance of rodent neurons to degeneration in genetic models of PD. Using GBA1-linked PD as an example, we discuss cellular pathways that may predispose human neurons to degeneration in PD, including mitochondrial oxidant stress, elevated intracellular calcium, altered synaptic vesicle endocytosis, accumulation of oxidized dopamine and neuromelanin. Recent studies have suggested that a combination of mitochondrial oxidant stress and accumulation of oxidized dopamine contribute to dysfunction of nigral neurons in various genetic and sporadic forms of PD. We also briefly summarize the development of targeted therapies for GBA1-associated synucleinopathies and highlight that modulation of wildtype GCase activity serves as an important target for the treatment of genetic and idiopathic forms of PD and dementia with Lewy bodies.