RNA metabolism in ALS: When normal processes become pathological

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons. While the exact molecular and cellular basis for motor neuron death is not yet fully understood, the current conceptualization is that multiple aberrant biological processes contribute. Among these, one of the most compelling is based on alterations of RNA metabolism. In this review, we examine how the normal process of cellular response to stress leading to RNA stress granule formation might become pathological, resulting in the formation of stable protein aggregates. We discuss the emerging roles of post-translational modifications of RNA binding proteins in the genesis of these aggregates. We also review the contemporary literature regarding the potential role for more widespread alterations in RNA metabolism in ALS, including alterations in miRNA biogenesis, spliceosome integrity and RNA editing. A hypothesis is presented in which aberrant RNA processing, modulated through pathological stress granule formation as a reflection of either mutations within intrinsically disordered or prion-like domains of critical RNA binding proteins, or the post-translational modification of RNA binding proteins, contributes directly to motor neuron death.

Key words::

• ALS
• RNA metabolism
• stress granule
• neuronal cytoplasmic inclusions
• post-translational modifications

Acknowledgements

We are grateful to Kevin Cheung for his critical reading of the manuscript and Wencheng Yang for his assistance with the immunohistochemistry images. MJS research is supported by the Canadian Institutes for Health Research (CIHR), the ALS Society of Canada and the Michael Halls Endowment.

Declaration of interest: The authors declare that they have no competing interests. The authors alone are responsible for the content and writing of the paper.