Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies
| Autor: | Ana Fernández-Villegas, Gabriele S. Kaminski Schierle, Marcus Fantham, Janin Lautenschläger, Amberley D. Stephens, Sara Wagner-Valladolid, James D. Manton, Eric J. Rees, Colin Hockings, Ajay Kumar Mishra, Clemens F. Kaminski, Meng Lu |
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| Přispěvatelé: | Lautenschläger, Janin [0000-0001-7788-7074], Stephens, Amberley D [0000-0002-7303-6392], Manton, James D [0000-0001-9260-3156], Kaminski Schierle, Gabriele S [0000-0002-1843-2202], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteases amyloid-β (Aβ ) Amyloid HtrA2/Omi Nerve Tissue Proteins Mitochondrion Protein aggregation Biochemistry protein aggregation Rats Sprague-Dawley 03 medical and health sciences α-synuclein neurodegenerative disease amyloid-β (AB) Cell Line Tumor medicine Animals Humans Molecular Biology protein homeostasis Lon peptidase 1 mitochondrial Amyloid beta-Peptides 030102 biochemistry & molecular biology Serine-Arginine Splicing Factors Chemistry Neurodegeneration neurodegeneration HtrA serine peptidase 2 Lon protease Molecular Bases of Disease Parkinson Disease Cell Biology High-Temperature Requirement A Serine Peptidase 2 medicine.disease Peptide Fragments 3. Good health Cell biology Mitochondria Rats α-synuclein (a-synuclein) Cytosol 030104 developmental biology Proteostasis alpha-Synuclein Female |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies. |
| Databáze: | OpenAIRE |
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