Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease.

Srinivasa Subramaniam

doi:10.15698/cst2021.06.251

Abstract

A ribosome typically moves at a particular rate on a given mRNA transcript to decode the nucleic acid information required to synthesize proteins. The speed and directionality of the ribosome movements during mRNA translation are determined by the mRNA sequence and structure and by various decoding factors. However, the molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Recent studies have indicated that defects in protein synthesis occur in various neurodegenerative diseases, but the mechanistic details are unclear. This is a major problem because identifying the factors that determine protein synthesis defects may offer new avenues for developing therapeutic remedies for currently incurable diseases like neurodegenerative disorders. Based on our recent study (Eshraghi et al., Nat Commun 12(1):1461; doi: 10.1038/s41467-021-21637-y), this short commentary will review the mechanistic understanding of Huntingtin (HTT)-mediated ribosome stalling indicating that central defects in protein synthesis in Huntington disease (HD) are orchestrated by jamming of ribosomes on mRNA transcripts.

Highlights

A new mechanism of HTT action in regulating ribosome movement is revealed in our recent report by Eshraghi et al, in which we show that both wildtype HTT and mutant HTT (mHTT) can bind to ribosomes and slow down ribosome movement; mHTT binds much stronger
We found an interesting accumulation of ribosomes at the 5’ position on the mRNAs of Huntington disease (HD) cells that expressed both copies of mHTT, but a 3’ accumulation of ribosomes on mRNAs of HD cells expressing one copy of mHTT
No evidence presently indicates a particular “signature” of mRNAs whose ribosome occupancy is altered in HD; this differential ribosome occupancy indicates that the amount of mHTT will determine the ribosome distribution across the various mRNA types

Summary

Introduction

A new mechanism of HTT action in regulating ribosome movement is revealed in our recent report by Eshraghi et al, in which we show that both wildtype HTT (wtHTT) and mHTT can bind to ribosomes and slow down ribosome movement; mHTT binds much stronger. The molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Recent studies have indicated that defects in protein synthesis occur in various neurodegenerative diseases, but the mechanistic details are unclear.

Results

Conclusion