In a 6-OHDA rat model of levodopa-induced dyskinesia, striatal ATG14 overexpression enhanced SNARE-dependent autophagosome-lysosome fusion, promoted ΔFosB degradation, and reduced dyskinesia, effects that were blocked by the autophagy inhibitor chloroquine.

This work pinpoints ATG14/SNARE-driven autophagy as a mechanistic and actionable target to mitigate LID, offering a translational route for developing autophagy-enhancing or gene-based interventions to treat dyskinesia in Parkinson's disease patients.

The chronic accumulation of ΔFosB in striatal medium spiny neurons has been implicated as a pivotal contributor to the pathogenesis of levodopa-induced dyskinesia (LID). While recent studies have implicated autophagy in the degradation of ΔFosB and the amelioration of LID, the precise mechanisms remain elusive. We induced LID in a unilateral 6-hydroxydopamine-lesioned parkinsonism rat model via chronic levodopa treatment. To modulate the autophagy pathway, we overexpressed ATG14 in the striatum of LID rats and administered chloroquine, an autophagy inhibitor, peripherally. We assessed LID severity using abnormal involuntary movements (AIMs) scores. Western blotting, real-time quantitative polymerase chain reaction, immunofluorescence, immunohistochemistry, transmission electron microscopy, and Golgi staining were employed to measure autophagy flux, synaptic alterations, and ΔFosB levels. Chronic levodopa treatment reduced ATG14 and SNARE complex (STX17, SNAP29, and VAMP8) levels, disrupted their interaction, impaired autophagy flux, affected synaptic function, and led to ΔFosB accumulation in the striatum of PD rats. Upregulating ATG14 in the striatum of LID rats improved AIMs scores, facilitated SNARE-mediated autophagosome-lysosome fusion, restored synaptic deficits, and promoted ΔFosB degradation. However, these beneficial effects of ATG14 upregulation were negated by chloroquine administration. Our findings suggest that upregulating ATG14 enhances SNARE formation, promoting autophagy flux and thereby reducing LID occurrence by facilitating ΔFosB degradation.