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Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2020
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1083351X and 00219258
- Volume :
- 295
- Issue :
- 30
- Database :
- OpenAIRE
- Journal :
- The Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....0c7e7eeeea451c96a4055d8c3caf92ea