Aquaporin-4 mis-localization decreases glymphatic clearance of α-synuclein in an alpha-syntrophin knock out mouse model and promotes α-synuclein pathology and aggregate propagation

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The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death but also contribute to disease progression by seeding the formation of additional aggregates in neighbouring cells. The mechanisms driving intercellular transmission of aggregates remain unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular aquaporin-4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with aquaporin-4 mis-localization throughout the grey matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular aquaporin-4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propagation using pre-formed fibril injection, we observed that loss of perivascular aquaporin-4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that aquaporin-4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy body dementia and Parkinson's disease.

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