Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.

Thyroid dysfunction affects 1–4% of the population worldwide, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that KCNQ1 and KCNE2 form a TSH-stimulated, constitutively-active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 impaired thyroid iodide accumulation up to 8-fold, impaired maternal milk ejection and halved milk T4 content, causing hypothyroidism, 50% reduced litter size, dwarfism, alopecia, goiter, and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by T3/T4 administration to pups, by supplementing dams with T4 pre- and postpartum, or by pre-weaning surrogacy with Kcne2+/+ dams; conversely these symptoms were elicited in Kcne2+/+ pups by surrogacy with Kcne2−/− dams. The data identify a critical thyrocyte K+ channel, provide a possible novel therapeutic avenue for thyroid disorders, and predict an endocrine component to some previously-identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.

No abstract