Abstract 1154 | | | | | EIF4G1 mutations in familial parkinsonism | | | | M.-C. Chartier-Harlin1,2, J. Dachsel3, M. Hulihan3, J. Kachergus3, F. Lepretre1, E. Le Rhun2, E. Mutez1,2, S. Lincoln3, O. Ross3, C. Vilariño-Güell3, A. Yanagiya4, N. Sonenberg4, P. Lockhart5, Z. Wszolek6, J. Aasly7, R. Frigerio8, D. Maraganore8, T. Lynch9, A. Ferraris10, E.-M. Valente10, A. Destée2, M. Farrer3 | | 1EA2683 MENRT, 2CHRU de Lille, Univ Lille, Lille, France, 3Neuroscience, Mayo Clinic, Jacksonville, FL, USA, 4Biochemistry, McGill University, Montreal, QC, Canada, 5Bruce Lefroy Centre for Genetic Health Research, Royal Children's Hospital, Melbourne, VIC, Australia, 6Neurology, Mayo Clinic, Jacksonville, FL, USA, 7Neurology, St Olavs Hospital, Trondheim, Norway, 8Neurology, Mayo Clinic, Rochester, MN, USA, 9Neurology, Mater Private Hospital, Dublin, Ireland, 10Neurogenetics Unit, CSS-Mendel Institute, Rome, Italy | | | | Genome-wide linkage analysis highlights chromosome 3q26-27 as new genetic locus for familial parkinsonism (LOD>3.0), consistent with a clinical diagnosis of late-onset idiopathic Parkinson's disease (PD). Comprehensive gene sequencing in the linked interval and segregation analysis of all variants directly implicates eukaryotic initiation factor (eIF) 4G1 p.R1205H in disease pathogenesis. Families originate from France, Ireland, Italy and the US and all affected carriers appear to have the same ancestral haplotype. The mutation is absent from unaffected age and ethnically matched control subjects (n=4000). eIF4G1 is the scaffold for a tripartite complex of eIF4E and eIF4A, activated as eIF4F, that binds mRNA and eIF3e, ultimately to form the 48S initiation complex. Co-immunoprecipitation studies demonstrate eIF4G1 p.R1205H perturbs eIF3e but not eIF4A binding. While the precise mechanism underlying the selective vulnerability of dopaminergic neurons remains to be elucidated, eIF4G1 helps regulate translation of specific mRNAs in response to stress, growth factors and nutrient availability. Generally, depletion of eIF4G1 impairs nutrient sensing and mitochondrial bioenergetics while promoting autophagy. In contrast eIF4G1 overexpression releases mRNA translation from mammalian target of rapamycin complex 1 (mTOR) signaling and is associated with increased transformation and malignancy. EIF4G1 mutations in familial parkinsonism provide genetic validation of a molecular signaling pathway implicated in LRRK2-parkinsonism (4E-BP phosphorylation and release of eIF4E) and L-DOPA-induced dyskinesia (by activation of striatal extracellular signal-related kinase). Opportunities for novel therapeutic approaches will be discussed. | | |
|
|