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FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS].
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2019 Jun 01; Vol. 1865 (6), pp. 1379-1388. Date of Electronic Publication: 2019 Feb 13. - Publication Year :
- 2019
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Abstract
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats (premutation) in FMR1. These CGG repeats are Repeat Associated non-ATG (RAN) translated into a small and pathogenic protein, FMRpolyG. The cellular and molecular mechanisms of FMRpolyG toxicity are unclear. Various mitochondrial dysfunctions have been observed in FXTAS patients and animal models. However, the causes of these mitochondrial alterations are not well understood. In the current study, we investigated interaction of FMRpolyG with mitochondria and its role in modulating mitochondrial functions. Beside nuclear inclusions, FMRpolyG also formed small cytosolic aggregates that interact with mitochondria both in cell and mouse model of FXTAS. Importantly, expression of FMRpolyG reduces ATP levels, mitochondrial transmembrane potential, mitochondrial supercomplexes assemblies and activities and expression of mitochondrial DNA encoded transcripts in cell and animal model of FXTAS, as well as in FXTAS patient brain tissues. Overall, these results suggest that FMRpolyG alters mitochondrial functions, bioenergetics and initiates cell death. The further study in this direction will help to establish the role of mitochondria in FXTAS conditions.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Adenosine Triphosphate biosynthesis
Aged
Aged, 80 and over
Animals
Ataxia metabolism
Ataxia pathology
Cell Line, Tumor
Cerebellum metabolism
Cerebellum pathology
DNA, Mitochondrial genetics
DNA, Mitochondrial metabolism
Disease Models, Animal
Electron Transport Chain Complex Proteins metabolism
Energy Metabolism genetics
Fragile X Mental Retardation Protein chemistry
Fragile X Mental Retardation Protein metabolism
Fragile X Syndrome metabolism
Fragile X Syndrome pathology
Gene Expression
HEK293 Cells
Humans
Membrane Potential, Mitochondrial genetics
Mice
Mice, Transgenic
Mitochondria metabolism
Mitochondria pathology
Neurons metabolism
Neurons pathology
Protein Aggregates genetics
RNA, Messenger metabolism
Tremor metabolism
Tremor pathology
Ataxia genetics
Electron Transport Chain Complex Proteins genetics
Fragile X Mental Retardation Protein genetics
Fragile X Syndrome genetics
Mitochondria genetics
RNA, Messenger genetics
Tremor genetics
Trinucleotide Repeat Expansion
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1865
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 30771487
- Full Text :
- https://doi.org/10.1016/j.bbadis.2019.02.010