Targeting DYNC1I1 attenuates Parkinsonian neurodegeneration and α-synuclein accumulation in cellular and mouse models.

OBJECTIVE

To investigate the effects of targeting DYNC1I1 in cellular and mouse models of Parkinson's disease (PD).

METHODS

The scRNA-seq dataset GSE243639 was analyzed to prioritize autophagy- and transport-related candidate genes in post-mortem substantia nigra samples from patients with PD and controls. SH-SY5Y cells were treated with 1 mM MPP⁺ for 48 h, and male C57BL/6 mice received MPTP at 30 mg/kg/day for 5 consecutive days. DYNC1I1 was silenced with siRNA in cells and targeted with AAV-DYNC1I1 in mice. Autophagic-lysosomal status was evaluated using tandem mCherry-GFP-LC3B fluorescence and autophagy- and lysosome-related markers. Motor performance was assessed using the pole and rotarod tests.

RESULTS

DYNC1I1 was prioritized as a candidate gene on the basis of PD-associated differential expression, overlap with autophagy-related genes, enrichment in a dopaminergic neuron-related subpopulation, and biological relevance to intracellular transport. In MPP⁺-treated cells, DYNC1I1 knockdown reduced α-synuclein accumulation and phosphorylation and improved autophagic-lysosomal marker profiles. In MPTP-treated mice, AAV-DYNC1I1 treatment improved motor performance and TH-positive signal and reduced α-synuclein pathology and autophagic-lysosomal impairment. AAV-DYNC1I1 treatment was also associated with higher p-PI3K/PI3K and p-AKT/AKT ratios.

CONCLUSIONS

DYNC1I1-targeting interventions attenuated PD-related phenotypes in cellular and mouse models. The observed effects were accompanied by improved autophagic-lysosomal marker profiles and increased PI3K/AKT phosphorylation.