ORCID Profile
0000-0003-2093-7389
Current Organisation
INSERM
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Publisher: EMBO
Date: 16-10-2015
Abstract: Mutations in the PTEN ‐induced kinase 1 ( PINK 1) are causative of autosomal recessive Parkinson's disease ( PD ). We have previously reported that PINK 1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser 65 ) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK 1‐dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub‐family of Rab GTP ases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser 111 ) in response to PINK 1 activation. Using phospho‐specific antibodies raised against Ser 111 of each of the Rabs, we demonstrate that Rab Ser 111 phosphorylation occurs specifically in response to PINK 1 activation and is abolished in HeLa PINK 1 knockout cells and mutant PINK 1 PD patient‐derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTP ase Ser 111 phosphorylation is not directly regulated by PINK 1 in vitro and demonstrate in cells the time course of Ser 111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser 65 . We further show mechanistically that phosphorylation at Ser 111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor ( GEF ), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK 1 is able to regulate the phosphorylation of Rab GTP ases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser 111 may represent novel biomarkers of PINK 1 activity in vivo . Our findings also suggest that disruption of Rab GTP ase‐mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2022
DOI: 10.1038/S41531-022-00400-0
Abstract: Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson’s disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients. We address this gap by identifying the gene dysregulation of live midbrain neurons reprogrammed in vitro from the skin cells of 42 in iduals, including sporadic and familial PD patients and matched healthy controls. To minimize bias resulting from neuronal reprogramming and RNA-seq methods, we developed an analysis pipeline integrating PD transcriptomes from different RNA-seq datasets (unsorted and sorted bulk vs. single-cell and Patch-seq) and reprogramming strategies (induced pluripotency vs. direct conversion). This PD cohort’s transcriptome is enriched for human genes associated with known clinical phenotypes of PD, regulation of locomotion, bradykinesia and rigidity. Dysregulated gene expression emerges strongest in pathways underlying synaptic transmission, metabolism, intracellular trafficking, neural morphogenesis and cellular stress/immune responses. We confirmed a synaptic impairment with patch-cl ing and identified pesticides and endoplasmic reticulum stressors as the most significant gene-chemical interactions in PD. Subsequently, we associated the PD transcriptomic profile with candidate pharmaceuticals in a large database and a registry of current clinical trials. This study highlights human transcriptomic pathways that can be targeted therapeutically before the irreversible neuronal loss. Furthermore, it demonstrates the preclinical relevance of unbiased large transcriptomic assays of reprogrammed patient neurons.
Publisher: Wiley
Date: 07-05-2022
DOI: 10.1002/ANA.26366
Abstract: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus . Whole‐exome and whole‐genome sequencing were performed in families linked to SCA25 , including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 ( PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25 . An additional nonsense variant was detected in an unrelated in idual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1‐domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double‐stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response. This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022 :122–137
Publisher: Informa UK Limited
Date: 02-01-2016
No related grants have been discovered for Olga Corti.