![]() Importantly, glial cells have been implicated in a series of neurodegenerative diseases including PD and many PD risk genes are also expressed in glial cells, further shedding light on the importance of glia in maintaining neuronal homeostasis. ![]() Nonetheless, in the past decades, numerous studies demonstrated that glia maximize their contact with neurons and actively contribute to almost every aspect of neuronal development and function, including neurogenesis, axon guidance and ensheathment, synaptic connection and plasticity, trophic supports, elimination of dying neurons, maintaining ionic balance, and blood–brain barrier (BBB) formation. Role of Glia in PDĪlthough glia outnumber neurons in the CNS, they were originally considered to be the inert “glue” (Greek “glia”) that fill in the space between neurons and play a passive supporting role due to the lack of electrical excitability. ![]() These genes help us to comprehend PD processes at cellular and molecular levels ( Table 1). Genome-wide association studies (GWAS) also suggest that both adaptive and innate immunity may play a role in PD pathogenesis. Accordingly, genes including SCNA, Parkin, leucine-rich repeat kinase 2 ( LRRK2), phosphatase and tensin homolog deleted on chromosome 10-induced putative kinase 1 ( PINK1), glucocerebrosidase ( GBA), vacuolar protein sorting 35 ( VPS35), and DJ-1 are linked to genetic variants that directly contribute to PD. The evidence consistently suggests that a higher risk of PD is associated with a number of environmental factors, including the area of residence, occupation, exposure to metals, pesticide and herbicide exposure, and so on. Īlthough the primary cause of PD cases appears to be spontaneous and widespread, most experts agree that the pathophysiology of this disease is profoundly influenced by the combination of genetic and environmental factors and that how genes and the environment interact can be very complicated. The accumulating evidence suggests that the increase in oxidative stress would exacerbate the development of PD. The formation of LBs always is connected with the induction of reactive oxygen species (ROS) and the generation of superoxide radical anions, hydrogen peroxide, and hydroxyl radicals. Importantly, the spread pattern of LBs pathology correlates with the progression of PD clinical symptoms, which is also the basis of the Braak staging system. Another pathological feature of PD is the formation of Lewy bodies (LBs) and Lewy neurites (LNs), which are cytoplasmic spherical protein inclusion bodies mainly composed of α-synuclein (α-syn) ( Figure 1D). These DA neurons are required for normal motor function, the death of which lead to bradykinesia, tremor, and rigidity. The pathological hallmark of PD is the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) ( Figure 1D). Upon ageing, PD patients exhibit worsening central nervous system (CNS) symptoms cultivating to defects in the motor system. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. 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. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. 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. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. 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. Parkinson’s disease (PD) is a progressive neurodegenerative disorder.
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