Autophagy–lysosome pathway alterations and alpha-synuclein up-regulation in the subtype of neuronal ceroid lipofuscinosis, CLN5 disease
| Autor: | Melissa Feuerborn, Alexa R. Wilden, Joshua A. Molina, Stella Y. Lee, Jessie Adams, Theodore Budden, Babita Adhikari |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell lcsh:Medicine Biology Article HeLa 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Neuronal Ceroid-Lipofuscinoses Lysosome Autophagy medicine Humans lcsh:Science Alpha-synuclein Gene knockdown Multidisciplinary lcsh:R Lysosome-Associated Membrane Glycoproteins Fibroblasts medicine.disease biology.organism_classification Up-Regulation Cell biology 030104 developmental biology medicine.anatomical_structure nervous system chemistry alpha-Synuclein lcsh:Q Neuronal ceroid lipofuscinosis Lysosomes Microtubule-Associated Proteins 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-36379-z |
| Popis: | Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders. CLN5 deficiency causes a subtype of NCL, referred to as CLN5 disease. CLN5 is a soluble lysosomal protein with an unclear function in the cell. Increased levels of the autophagy marker protein LC3-II have been reported in several subtypes of NCLs. In this report, we examine whether autophagy is altered in CLN5 disease. We found that the basal level of LC3-II was elevated in both CLN5 disease patient fibroblasts and CLN5-deficient HeLa cells. Further analysis using tandem fluorescent mRFP-GFP-LC3 showed the autophagy flux was increased. We found the alpha-synuclein (α-syn) gene SNCA was highly up-regulated in CLN5 disease patient fibroblasts. The aggregated form of α-syn is well known for its role in the pathogenicity of Parkinson’s disease. Higher α-syn protein levels confirmed the SNCA up-regulation in both patient cells and CLN5 knockdown HeLa cells. Furthermore, α-syn was localized to the vicinity of lysosomes in CLN5 deficient cells, indicating it may have a lysosome-related function. Intriguingly, knocking down SNCA reversed lysosomal perinuclear clustering caused by CLN5 deficiency. These results suggest α-syn may affect lysosomal clustering in non-neuronal cells, similar to its role in presynaptic vesicles in neurons. |
| Databáze: | OpenAIRE |
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