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

Nethaji Thiyagarajan, Ross Ferguson, Vasanta Subramanian, K Ravi Acharya

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Article number1121
Number of pages14
JournalNature Communications
Volume3
DOIs
StatusPublished - 9 Oct 2012

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Advanced Launch System (STS)
neurons
Neurons
cultured cells
Parkinson disease
Cells
Cell Line
Pancreatic Ribonuclease
mutations
Ribonucleases
angiogenin
Parkinson Disease
Catalytic Domain
Mutation

Keywords

  • amyotrophic lateral sclerosis
  • Angiogenin
  • neurons
  • stress granules
  • ALS mutants
  • crystal structure

Cite this

Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons. / Thiyagarajan, Nethaji; Ferguson, Ross; Subramanian, Vasanta; Acharya, K Ravi.

In: Nature Communications, Vol. 3, 1121, 09.10.2012.

Research output: Contribution to journalArticle

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