The Parkinson-Causing LRRK2 Mutation G2019S Impairs the Physiological Tetramerization of Α-Synuclein in Human Neurons

α-Synuclein aggregation in Lewy bodies/neurites is the defining feature of familial and ‘sporadic’ Parkinson’s disease. We previously identified helical αSyn tetramers in normal cells. PD-causing αSyn mutations lower the tetramer:monomer (T:M) ratio, associated with αSyn hyperphosphorylation and cytotoxicity in cultured neurons and a progressive motor syndrome of resting tremor and gait deficits in transgenic mice. We asked whether LRRK2 mutations, the most common genetic cause of what were previously considered sporadic PD cases, also alter αSyn tetramer homeostasis. iPSC-derived patient neurons carrying the most prevalent LRRK2 mutation (G2019S) had decreased T:M ratios and pSer129 hyperphosphorylation of their endogenous αSyn. A LRRK2 kinase inhibitor restored the T:M ratio and prevented hyperphosphorylation of αSyn and the LRRK2-substrate Rab10. With the discovery that PD-causing mutations of glucocerebrosidase in Gaucher’s carriers also decrease T:M ratios, our findings indicate that three distinct genetic forms of PD involve life-long destabilization of αSyn tetramers as a common pathogenic mechanism in PD.