Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins including α-synuclein in Parkinson’s disease, tau in Alzheimer’s disease and polyglutamine-expanded proteins such as mutant huntingtin (HTT) in Huntington’s disease. These protein aggregates and associated dysregulated autophagy are characteristic pathological hallmarks of neurodegenerative disease. Impaired autophagosome formation, trafficking or lysosomal degradation have all been implicated in the failure to remove these proteins, exacerbating neuronal loss.
Consistent with this, pharmacological or genetic interventions that boost neuronal autophagy ameliorate aggregate burden and neurodegenerative phenotypes in various disease models. Despite this compelling evidence, translating autophagy modulation into effective therapies has proven challenging.
It has been previously found that microglia secreted factors impair neuronal autophagy. CCL3, CCL4 and CCL5 have been identified as causative chemokines. In this study led by Matea Rob from the Rubinsztein lab and UK Dementia Research Institute, researchers screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against the expectation of identifying negative regulators, researchers found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro and in vivo. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.