Alpha-Synuclein Blocks Endoplasmic Reticulum Co-Translational Protein Translocation Early in Parkinson’s Disease

The primary mechanism and subcellular localization of alpha-synuclein toxicity in Parkinson’s disease pathogenesis remain unknown. Researchers investigated the effects of pathological alpha-synuclein on human iPSC-derived dopaminergic neurons, using proteomic and transcriptomic profiling to analyze changes in protein expression and cellular function. The study found that misfolded alpha-synuclein proteoforms are associated with impaired translocon function at the endoplasmic reticulum (ER), leading to defective organelle function such as reduced lysosomal acidification. This impairment causes increased extracellular vesicle release of alpha-synuclein, exacerbating disease progression. The researchers also identified interactions between alpha-synuclein and Sec61A, a translocon complex responsible for protein transport across the ER membrane. These interactions interfere with co-translational translocation of ER-processed proteins, including vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B. The study suggests that alpha-synuclein pathology disrupts diverse organelle-associated proteins, providing a unifying mechanistic link between alpha-synuclein toxicity and Parkinson’s disease risk. The findings also offer a therapeutic rationale for proteasomal activation in early Parkinson’s disease treatment.