ASTROCYTIC MITOPHAGY PROTECTS AGAINST PROTEIN AGGREGATION-MEDIATED BIOENERGETIC STRESS AND MOTOR DISCOORDINATION

Astrocytes play critical roles in brain homeostasis, and their dysfunction contributes to different neurodegenerative diseases, such as Huntington’s disease (HD). The anomalous expansion of polyglutamine in huntingtin (HTT) protein provokes its intracellular aggregation and mitochondrial dysfunction, a typical feature of HD. Activating proteolysis through, e.g., autophagy, may therefore be a promising strategy against certain neurodegenerative disorders. On the other hand, cannabinoids have been shown to modulate autophagy¹,^2,3 and it has been shown to be a promising strategy in preclinical models of several neurological diseases, including HD¹. However, the connection between cannabinoids, autophagy and HD seems therefore controversial. Since autophagy is an active process in astrocytes⁵, and these cells express CB1R⁶, here we investigated whether ∆9-tetrahydrocannabinol (THC), a bioactive component of C. sativa, restores proteostasis and mitophagy in astrocytes expressing mutant huntingtin (mtHTT). We found that THC activates cannabinoid receptor-1 (CB1R) signaling to enhance autophagic flux, facilitating lysosome-dependent clearance of aberrant mitochondria and mtHTT aggregates. Proteomic and functional analyses revealed that THC promotes mitochondrial remodeling through mitophagy, and respiratory chain supercomplex assembly, leading to improved bioenergetics. In vivo, astrocyte-specific expression of mtHTT in mice recapitulates key HD features, including gliosis and motor deficits, which were attenuated by THC treatment. Our findings establish a glia-driven framework for neuroprotection and identify cannabinoids as potential modulators of astrocytic mitophagy. We also highlight the therapeutic relevance of targeting astrocytic signaling to complement neuron-centric strategies in neurodegenerative diseases.