1: RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration.

Science Translational Medicine

08 Nov 2017: Vol.9, Issue 415, eaah5436

Daisuke Ito, Mami Hatano and Norihiro Suzuki

Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that leads to respiratory failure within a few years. In 2006, the RNA-binding protein TDP-43 was identified as a groundbreaking causative molecule that revolutionized the concept of ALS. Since then, causative genes for ALS have been identified one after another, and their molecular mechanisms have been dramatically elucidated. While ALS was previously considered a disease that selectively affects motor neurons, it is now understood to be a disease spectrum with diverse phenotypes, co-occurring with conditions such as frontotemporal dementia (a form of young-onset dementia) and musculoskeletal diseases. The physiological functions of the identified causative genes for ALS converge on intracellular mechanisms such as RNA metabolism and protein quality control. It has become clear that the molecular pathology of ALS lies in the failure of these two molecular mechanisms. In this review, based on our own basic research, we provide an overview of the topics mentioned above and discuss the potential for developing disease-modifying drugs to overcome neurodegenerative diseases.

(Daisuke Ito, Department of Neurology, 71)

Abnormal Cytoplasmic Localization of RNA-Binding Proteins and the Molecular Pathology of ALS

It is suggested that the RNA-binding proteins TDP-43 and FUS, when accumulated in the cytoplasm, disrupt RNA quality control mechanisms and trigger a neurodegenerative cascade through inappropriate RNA granule formation and subsequent inclusion body formation. Furthermore, various ALS gene mutations are thought to promote the cytoplasmic translocation and accumulation of RNA-binding proteins.