1. FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]
- Author
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Milton Roy, Dhruv Gohel, Nicolas Charlet-Berguerand, Kritarth Singh, Lakshmi Sripada, Rajesh Singh, Darshan Kotadia, Flora Tassone, Paresh Prajapati, University of Baroda, India, University of Kentucky, University of California [Davis] (UC Davis), University of California, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Mitochondrial DNA ,Programmed cell death ,Ataxia ,[SDV]Life Sciences [q-bio] ,Gene Expression ,Mice, Transgenic ,Mitochondrion ,Biology ,DNA, Mitochondrial ,Fragile X Mental Retardation Protein ,Mice ,Protein Aggregates ,03 medical and health sciences ,Adenosine Triphosphate ,0302 clinical medicine ,Cell Line, Tumor ,Cerebellum ,Tremor ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,Aged ,Aged, 80 and over ,Membrane Potential, Mitochondrial ,Neurons ,Respiratory chain complex ,medicine.disease ,FMR1 ,Mitochondria ,3. Good health ,Cell biology ,Disease Models, Animal ,Cytosol ,HEK293 Cells ,030104 developmental biology ,Electron Transport Chain Complex Proteins ,Fragile X Syndrome ,Molecular Medicine ,medicine.symptom ,Energy Metabolism ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery ,Fragile X-associated tremor/ataxia syndrome - 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.
- Published
- 2019