Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons

Abstract

Mutations in angiogenin ( ANG), a member of the ribonuclease A superfamily, are associated with amyotrophic lateral sclerosis (ALS; sporadic and familial) and Parkinson's disease. We have previously shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. Here we report the atomic resolution structure of native ANG and 11 ANG-ALS variants. We correlate the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. ANG-ALS variants that affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Our structure–function studies on these ANG-ALS variants are the first to provide insights into the cellular and molecular mechanisms underlying their role in ALS.

Abstract

Mutations in human angiogenin are implicated in the progression of amyotrophic lateral sclerosis. Thiyagarajan and colleagues show that structural differences between angiogenin variants affect neuronal survival, and the ability to induce stress granules in neuronal cell lines.