Researchers here note that the presence of α-synuclein protein aggregates, a characteristic feature of Parkinson's disease, contributes to the dysfunction of microglia. Microglia are innate immune cells of the brain, responsible not just for attacking pathogens and clearing debris, but also involved in maintaining the synaptic connections between neurons. Increasing attention is placed upon the age-related dysfunction of microglia as an important contribution to the progression of neurodegenerative diseases such as Parkinson's. Chronic inflammation in brain tissue is a feature of neurodegeneration, and much of that may be caused or amplified by changes that take place in the microglial population in response to the age-damaged tissue environment.
Parkinson's disease (PD) is an age-related neurodegenerative disorder, affecting about 2% of the population over 60. Pathologically, it is characterized by dopamine (DA) neuron losses and α-synuclein (α-Syn)-abundant Lewy body or neurites formation in the substantia nigra (SN). Additionally, microglia activation, along with excessive generation of inflammatory cytokines, is reported in the brains of PD patients and animal models.
α-Syn misfolding and aggregation are linked to PD pathology. Under pathological conditions, this synaptic protein can be released from neurons, propagating and spreading in the nervous system via cell autonomous and non-autonomous machinery. The natural state (monomer vs. tetramer) and the structure of neuron-released α-Syn is controversial. But it is well demonstrated that extracellular α-Syn activates microglia and inflammatory response, contributing to PD progression.
In this study, we reported an impairment of microglial autophagy caused by extracellular α-Syn via toll-like receptor 4 (Tlr4) and downstream p38 and Akt-mTOR signaling pathways and provided the evidence that conditional knockout of microglial autophagy-related gene 5 (Atg5) in mice enhanced the neuroinflammation and DA neuron losses in the midbrain and exacerbated the locomotor deficits in a viral-based α-Syn overexpression mouse model.
In sum, our findings demonstrate that α-Syn disrupts microglial autophagy initiation via Tlr4-dependent p38 and Akt-mTOR signaling and reveal that microglial autophagy impairment contributes to neuroinflammation and other PD pathogenesis. Therefore, the pharmacologic and genetic strategies that aim to modulate autophagy activity in the brain may become a potential venue for PD therapy.
Link: https://doi.org/10.1111/acel.13522
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