Targeting DYNC1I1 attenuates Parkinsonian neurodegeneration and α-synuclein accumulation in cellular and mouse models.
Targeting DYNC1I1 attenuates Parkinsonian neurodegeneration and α-synuclein accumulation in cellular and mouse models.
Where did the research take place?
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Hefei, CN · Author affiliation
Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.Location evidence
Bengbu, CN · Author affiliation
Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.Location evidence
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Original abstract
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.