Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson's disease-related fibril polymorphism

Lipid interaction with alpha-synuclein (alpha Syn) has been long implicated in the pathogenesis of Parkinson's disease (PD). However, it has not been fully determined which lipids are involved in the initiation of alpha Syn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of alpha Syn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological alpha Syn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of alpha Syn. Mutations in SYNJ1 accelerated the accumulation of alpha Syn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of alpha Syn via the dysregulation of its substrate PIP3, leading to the aggravation of alpha Syn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of alpha Syn inclusions. Indeed, in vitro protein-lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with alpha Syn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of alpha Syn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with alpha Syn. Taken together, PIP3 dysregulation promotes the pathological aggregation of alpha Syn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.

Automated summary

The functional loss of SYNJ1 leads to elevated levels of PIP3, which promotes the pathological aggregation of alpha Syn and increases the risk of developing Parkinson's disease. This relationship was confirmed through cellular and model organism experiments, as well as analysis of postmortem brain samples from PD patients. These findings suggest that PIP3 may be a promising target for interventions in Parkinson's disease.