Influence of microRNA deregulation on chaperone-mediated autophagy and α-synuclein pathology in Parkinson's disease
| Autor: | J M Cooper, M.C. Rodríguez-Oroz, Yiqi Seow, Anthony H.V. Schapira, Jose A. Obeso, Lydia Alvarez-Erviti |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Pathology Parkinson's disease Transcription Genetic Gene mutation Pathogenesis chemistry.chemical_compound 0302 clinical medicine Chaperone-mediated autophagy Genes Reporter Protein Isoforms Luciferases chaperone-mediated autophagy 0303 health sciences microRNA Amygdala/pathology HSP70 Heat-Shock Proteins/metabolism Parkinson Disease Amygdala Substantia Nigra Mitochondrial respiratory chain alpha-Synuclein Original Article Amygdala/metabolism Signal Transduction medicine.medical_specialty Immunology Substantia nigra Biology 03 medical and health sciences Cellular and Molecular Neuroscience α-synuclein Downregulation and upregulation Cell Line Tumor Lysosomal-Associated Membrane Protein 2 medicine Autophagy Humans HSP70 Heat-Shock Proteins RNA Messenger 030304 developmental biology Alpha-synuclein Lysosome-Associated Membrane Glycoproteins Cell Biology medicine.disease MicroRNAs chemistry Gene Expression Regulation Lewy Bodies 030217 neurology & neurosurgery |
| Zdroj: | Cell Death & Disease Dadun. Depósito Académico Digital de la Universidad de Navarra instname |
| ISSN: | 2041-4889 |
| Popis: | The presence of α-synuclein aggregates in the characteristic Lewy body pathology seen in idiopathic Parkinson's disease (PD), together with α-synuclein gene mutations in familial PD, places α-synuclein at the center of PD pathogenesis. Decreased levels of the chaperone-mediated autophagy (CMA) proteins LAMP-2A and hsc70 in PD brain samples suggests compromised α-synuclein degradation by CMA may underpin the Lewy body pathology. Decreased CMA protein levels were not secondary to the various pathological changes associated with PD, including mitochondrial respiratory chain dysfunction, increased oxidative stress and proteasomal inhibition. However, decreased hsc70 and LAMP-2A protein levels in PD brains were associated with decreases in their respective mRNA levels. MicroRNA (miRNA) deregulation has been reported in PD brains and we have identified eight miRNAs predicted to regulate LAMP-2A or hsc70 expression that were reported to be increased in PD. Using a luciferase reporter assay in SH-SY5Y cells, four and three of these miRNAs significantly decreased luciferase activity expressed upstream of the lamp-2a and hsc70 3'UTR sequences respectively. We confirmed that transfection of these miRNAs also decreased endogenous LAMP-2A and hsc70 protein levels respectively and resulted in significant α-synuclein accumulation. The analysis of PD brains confirmed that six and two of these miRNAs were significantly increased in substantia nigra compacta and amygdala respectively. These data support the hypothesis that decreased CMA caused by miRNA-induced downregulation of CMA proteins plays an important role in the α-synuclein pathology associated with PD, and opens up a new avenue to investigate PD pathogenesis. |
| Databáze: | OpenAIRE |
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