Regulation Of DNA Repeat Translation In Neurodegenerative Disease By Stress And eIF2alpha

Pathology department and Brain Science Institute researcher Shuying Sun and her group have uncovered a mechanism by which genetic alterations common in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and some dementias may promote loss of neurons. They focus on how aberrant proteins are produced in disease, and their findings suggest a possible new point of therapeutic intervention. Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both ALS and frontotemporal dementia (FTD). Unconventional translation of the repeat-containing RNA produces multiple toxic poly-dipeptides, which contribute to neurodegeneration. The new study demonstrates that the repeat translation is upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response. Compounds inhibiting phospho-eIF2α-signaling pathways were shown to suppress translation of the repeats. Since the poly-dipeptides can themselves induce stress, this could trigger a feedforward loop with initial repeat-mediated toxicity enhancing the repeat translation and subsequent production of additional poly-dipeptides, thereby driving relentless disease progression. A method perturbing this loop might reduce or delay neurodegeneration and hold therapeutic promise in C9ORF72-ALS/FTD. The study was recently published in Nature Communications (

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