Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2
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Published on: April 24, 2021
Georg Auburger1, Nesli-Ece Sen1, David Meierhofer2
1Department of Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
Abstract:
Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast.
Insights
Ataxin-2 (ATXN2) protein is vital for cellular functions and linked to neurodegenerative diseases. Reducing ATXN2 levels effectively prevents motor neuron and cerebellar atrophy in model organisms.
Area of Science:
- Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Ataxin-2 (ATXN2) homologs are conserved across eukaryotes, involved in mRNA repair, translation, and cellular metabolism.
- ATXN2 regulates cell size, protein synthesis, and nutrient storage via mTORC1 signaling.
- ATXN2 is essential for specific liver mitochondrial enzymes and the mitochondrial repair factor PINK1.
Purpose of the Study:
- To investigate the multifaceted roles of Ataxin-2 (ATXN2) in cellular physiology.
- To explore the connection between ATXN2 function and human neurodegenerative diseases.
Main Methods:
- Analysis of ATXN2 homologs in eukaryotic organisms.
- Investigating ATXN2's role in mRNA processing and mTORC1 signaling pathways.
- Studying ATXN2's impact on mitochondrial function and stress granule formation.
- Evaluating the effects of ATXN2 depletion in mouse, fly, and yeast models of neurodegeneration.
Main Results:
- ATXN2 influences mRNA repair, translation, and cellular metabolism, including fat and glycogen storage.
- ATXN2 is required for the function of specific liver mitochondrial enzymes and PINK1.
- ATXN2 is upregulated during starvation and forms stress granules to manage RNA pathology.
- Depletion of ATXN2 demonstrated significant efficacy in preventing motor neuron and cerebellar atrophy in various model systems.
Conclusions:
- Ataxin-2 (ATXN2) plays critical roles in fundamental cellular processes and mitochondrial maintenance.
- The study highlights ATXN2's crucial involvement in neurodegenerative disease pathogenesis.
- Targeting ATXN2 presents a promising therapeutic strategy for preventing neuronal atrophy in neurodegenerative conditions.
