Abstract
The abnormal accumulation of alpha-synuclein (α-syn) aggregates in neurons and glial cells is widely known to be associated with many neurodegenerative diseases, including Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Mitochondrial dysfunction in neurons and glia is known as a key feature of α-syn toxicity. Studies aimed at understanding α-syn-induced toxicity and its role in neurodegenerative diseases have primarily focused on neurons. However, a growing body of evidence demonstrates that glial cells such as microglia and astrocytes have been implicated in the initial pathogenesis and the progression of α-Synucleinopathy. Glial cells are important for supporting neuronal survival, synaptic functions, and local immunity. Furthermore, recent studies highlight the role of mitochondrial metabolism in the normal function of glial cells. In this work, we review the complex relationship between glial mitochondria and α-syn-mediated neurodegeneration, which may provide novel insights into the roles of glial cells in α-syn-associated neurodegenerative diseases.
Highlights
Alpha synuclein (α-syn), first identified in 1988 by Maroteaux et al (1988), is a small protein that consists of 140 amino acids and encodes the human SNCA gene. α-syn is expressed in the central nervous system (CNS), and is localized in synapses and nuclei (Jakes et al, 1994)
Unlike Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA), Pure autonomic failure (PAF) is a rare sporadic neurodegenerative disease induced by dysfunction of autonomic nervous system (Thaisetthawatkul, 2016)
Choi et al (2020) showed that TLR4-nuclear factor κB (NF-κB)-p62-mediated selective autophagy activation in microglia was implicated in the clearance of neuronsecreted α-syn and this clearance mechanism was important for neuroprotective functions of microglia
Summary
Alpha synuclein (α-syn), first identified in 1988 by Maroteaux et al (1988), is a small protein that consists of 140 amino acids and encodes the human SNCA gene. α-syn is expressed in the central nervous system (CNS), and is localized in synapses and nuclei (Jakes et al, 1994). Unlike PD, DLB, and MSA, Pure autonomic failure (PAF) is a rare sporadic neurodegenerative disease induced by dysfunction of autonomic nervous system (Thaisetthawatkul, 2016) It is slowly progressive disease and caused by abnormal accumulation of α-syn (Thaisetthawatkul, 2016; Coon et al, 2019; Coon, 2020). Overexpression of wild-type human α-syn in oligodendrocytes induced mitochondrial dysfunction in transgenic mice, leading to oxidative stress in vivo and neuronal cell death (Stefanova et al, 2005). Microglia remove excess synapses in the developing brain and appear to play an important role in the wiring of the CNS (Jakel and Dimou, 2017) Under pathological conditions such as neurodegenerative diseases, infection and physical injury, microglia are activated. Choi et al (2020) showed that TLR4-NF-κB-p62-mediated selective autophagy activation in microglia was implicated in the clearance of neuronsecreted α-syn and this clearance mechanism was important for neuroprotective functions of microglia
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