Life science
Medical & healthcare, Drug development

Phosphatidylinositol‑3,4,5‑trisphosphate interacts with alpha‑synuclein and initiates its
aggregation and formation of Parkinson’s disease‑related fibril polymorphism
Department of Neurology, Graduate School of Medicine
Assistant Professor Kensuke Ikenaka

https://researchmap.jp/kensukeikenaka?lang=en

Professor Hideki Mochizuki				https://researchmap.jp/read0207787?lang=en

Life science

Abstract
Our group revealed that the accumulation of a phospholipid called
PIP3 in PD patients is the cause of abnormal aggregation of αsynuclein (αSyn) (Lewy bodies), which has been thought to be thecause of PD. Until now, it has been known that αSyn aggregates inabout 10% of PD patients is caused by the accumulation of a glycolipid called glucosylceramide in the brain, however, the causative
factors for remaining PD patients had not been elucidated.
In this study, the research group screened lipids that bind to αSyn
and promote its aggregation and found that PIP3 strongly binds toαSyn and forms aggregates that are similar in shape and character toαSyn aggregated that accumulate in the brain of PD patients. Furthermore, when PIP3 accumulation was reproduced in neurons and C elegans model, αSyn aggregates in intracellular organelles such as lysosomes and synaptic terminals, where αSyn aggregation is frequently
observed in PD patients. In brain tissue from deceased patients, PIP3
was found to co-aggregate with αSyn, with increased amounts of PIP3in areas where αSyn accumulates from the early stages of the disease.

▍ Significance of the research and Future perspective
Previous studies have largely focused on elucidating downstream
neurodegeneration caused by αSyn aggregates. In this study, wewere able to identify upstream factors that initiate αSyn aggregationin the patient brain. Future prospects include therapies that remove
the causes of PIP3 accumulation and/or inhibit the binding of PIP3 toαSyn, which may lead to the development of novel concepts for thetherapeutic agents as a preemptive treatment for PD.

▍ Background & Results

Lipid interaction with α-synuclein (αSyn) has been long implicated inthe pathogenesis of Parkinson’s disease (PD). However, it has not been
fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating theloss-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 αSyn
and its relation to PD. We first established a SYNJ1 knockout cell modeland found SYNJ1 depletion increases the accumulation of pathological
αSyn. 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 αSyn. Mutations in SYNJ1 accelerated
the accumulation of αSyn aggregation and induced locomotory defects
in the nematodes. These results indicate that functional loss of SYNJ1
promotes the pathological aggregation of αSyn via the dysregulation ofits substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3
itself or with PIP3 phosphatase inhibitor resulted in intracellular formationof αSyn inclusions. Indeed, in vitro protein–lipid overlay assay validated
that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates
the fibrillation of αSyn, 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 immunohistochemicaland lipidomic analyses on postmortem brain of patients with sporadic
PD showed increased PIP3 level and its colocalization with αSyn. Taken
together, PIP3 dysregulation promotes the pathological aggregation ofαSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.

P a t e n t
Choong, Chi-Jin; Mochizuki, Hideki; Ikenaka, Kensuke et al. Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates itsT r e a t i s e aggregation and formation of Parkinson’s disease-related fibril polymorphism. Acta Neuropathol. 2023, 145(5), 573-595.
doi: 10.1007/s00401-023-02555-3
URL
K e y w o r d parkinson’s disease, αsynuclein, protein aggregation, phosphatidylinositol-3-phosphate