Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons

alpha-Synuclein (alpha Syn) aggregation in Lewy bodies and neurites defines both familial and 'sporadic' Parkinson's disease. We previously identified alpha-helically folded alpha Syn tetramers, in addition to the long-known unfolded monomers, in normal cells. PD-causing alpha Syn mutations decrease the tetramer:monomer (T:M) ratio, associated with alpha Syn hyperphosphorylation and cytotoxicity in neurons and a motor syndrome of tremor and gait deficits in transgenic mice that responds in part to L-DOPA. Here, we asked whether LRRK2 mutations, the most common genetic cause of cases previously considered sporadic PD, also alter tetramer homeostasis. Patient neurons carrying G2019S, the most prevalent LRRK2 mutation, or R1441C each had decreased T:M ratios and pSer129 hyperphosphorylation of their endogenous alpha Syn along with increased phosphorylation of Rab10, a widely reported substrate of LRRK2 kinase activity. Two LRRK2 kinase inhibitors normalized the T:M ratio and the hyperphosphorylation in the G2019S and R1441C patient neurons. An inhibitor of stearoyl-CoA desaturase, the rate-limiting enzyme for monounsaturated fatty acid synthesis, also restored the alpha Syn T:M ratio and reversed pSer129 hyperphosphorylation in both mutants. Coupled with the recent discovery that PD-causing mutations of glucocerebrosidase in Gaucher's neurons also decrease T:M ratios, our findings indicate that three dominant genetic forms of PD involve life-long destabilization of alpha Syn physiological tetramers as a common pathogenic mechanism that can occur upstream of progressive neuronal synucleinopathy. Based on alpha Syn's finely-tuned interaction with certain vesicles, we hypothesize that the fatty acid composition and fluidity of membranes regulate alpha Syn's correct binding to highly curved membranes and subsequent assembly into metastable tetramers.

Automated summary

The study found that three major genetic forms of Parkinson's disease involve lifelong destabilization of alpha-synuclein physiological tetramers as a common pathogenic mechanism that may occur upstream of progressive neuronal synucleinopathy.