FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]

Dhruv Gohel, Lakshmi Sripada, Paresh Prajapati, Kritarth Singh, Milton Roy, Darshan Kotadia, Flora Tassone, Nicolas Charlet-Berguerand, Rajesh Singh

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
DOIs
StatePublished - Jan 1 2019

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Electron Transport
Mitochondria
Animal Models
Intranuclear Inclusion Bodies
Mitochondrial DNA
Neurodegenerative Diseases
Membrane Potentials
Energy Metabolism
Fragile X Tremor Ataxia Syndrome
Cell Death
Adenosine Triphosphate
Brain
Proteins

Keywords

  • FMRpolyG
  • FXTAS
  • Mitochondria
  • Mitochondrial supercomplexes (mSCs)
  • RAN translation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]. / Gohel, Dhruv; Sripada, Lakshmi; Prajapati, Paresh; Singh, Kritarth; Roy, Milton; Kotadia, Darshan; Tassone, Flora; Charlet-Berguerand, Nicolas; Singh, Rajesh.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, 01.01.2019.

Research output: Contribution to journalArticle

Gohel, Dhruv ; Sripada, Lakshmi ; Prajapati, Paresh ; Singh, Kritarth ; Roy, Milton ; Kotadia, Darshan ; Tassone, Flora ; Charlet-Berguerand, Nicolas ; Singh, Rajesh. / FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 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.",
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