Pathogenesis of α-Synuclein in Parkinson's Disease: From a Neuron-Glia Crosstalk Perspective

Parkinson's disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of alpha-synuclein (alpha-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of alpha-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of alpha-syn between neurons and glia, alpha-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, alpha-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.

Automated summary

Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of alpha-synuclein. Glial activation and neuroinflammation have been identified as new features of PD, and understanding the interaction between neurons and glia can provide insight into PD pathologies.