ArticleNPJ Parkinson's disease2022
Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons.
Article in NPJ Parkinson's disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Elevation of Stearoyl-Coenzyme A Desaturase and Monounsaturated Fatty Acids in Parkinson's Disease Serum.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.npj metabolic health and disease · 2026Article
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- Clinical Validation of α-Synuclein in Salivary Extracellular Vesicles as a Biomarker for Parkinson's Disease: A Longitudinal Study.European journal of neurology · 2026Article
- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
- Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.JCI insight · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- α-Synuclein Pathology Spreads in a Midbrain-Hindbrain Assembloid Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson's disease.NPJ Parkinson's disease · 2025Review
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- The Impact of LRRK2 G2019S on Parkinson's Disease: Clinical Phenotype and Treatment in Tunisian Patients.Journal of movement disorders · 2024Article
- RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.The Journal of cell biology · 2024Article
- Influence of Cigarette Aerosol in Alpha-Synuclein Oligomerization and Cell Viability in SH-SY5Y: Implications for Parkinson's Disease.ACS chemical neuroscience · 2024Article
- Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson's disease phenotypes.NPJ Parkinson's disease · 2024Article
- Alpha-synuclein dynamics bridge Type-I Interferon response and SARS-CoV-2 replication in peripheral cells.Biological research · 2024Article
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson's Disease.International journal of molecular sciences · 2023Review
- The interaction between the nervous system and the stomatognathic system: from development to diseases.International journal of oral science · 2023Review
- RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
α-Synuclein (αSyn) aggregation in Lewy bodies and neurites defines both familial and 'sporadic' Parkinson's disease. We previously identified α-helically folded αSyn tetramers, in addition to the long-known unfolded monomers, in normal cells. PD-causing αSyn mutations decrease the tetramer:monomer (T:M) ratio, associated with αSyn 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 αSyn 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 αSyn 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 αSyn physiological tetramers as a common pathogenic mechanism that can occur upstream of progressive neuronal synucleinopathy. Based on αSyn's finely-tuned interaction with certain vesicles, we hypothesize that the fatty acid composition and fluidity of membranes regulate αSyn's correct binding to highly curved membranes and subsequent assembly into metastable tetramers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.