Research Press Release

Neurodegeneration: Small-molecule strategy for neurodegenerative diseases

Nature

April 13, 2017

Therapies that reduce the levels of the protein ataxin-2 (ATXN2) help to improve symptoms in mouse models of amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2), report a pair of papers published online in Nature this week. It is hoped that the results could aid the development of treatments for these and other neurodegenerative disorders.

Abnormalities in the ataxin-2 protein have previously been implicated in both ALS and SCA2, leading researchers to question whether small, targeted molecules that affect the production of this protein could be used as a possible treatment. Stefan Pulst and colleagues highlight one such antisense oligonucleotide, ASO7, which decreased levels of the ataxin-2 protein, normalized the firing of abnormal neurons and improved motor function in two mouse models of SCA2. In a separate study, Aaron Gitler and colleagues found that treatment with a similar antisense oligonucleotide lowered levels of ataxin-2, improved motor function and extended the lifespan of mice in a mouse model of ALS.

Most patients with ALS have clumps of the potentially toxic protein TDP-43 in their brain and spinal cord. Previous studies in yeast and flies have shown that lowering levels of ataxin-2 can suppress TDP-43 toxicity. In the second study, Gitler and co-authors show how decreasing the levels of ataxin-2 can reduce the build-up of these TDP-43 aggregates in mice with ALS symptoms. Given that TDP-43 aggregates are also found in around half the patients with frontal temporal dementia, strategies that target ataxin-2 could prove useful in a broad range of neurodegenerative conditions, the authors speculate.

DOI:10.1038/nature22038 | Original article

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