Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.

Michael P Hart,Zhihui Sun,Alessandra Chesi,Aaron D Gitler,Zamia Diaz,Jonathan S Weissman,James Shorter,Xiaodong Fang

doi:10.1371/journal.pbio.1000614

Abstract

Author SummaryMany human neurodegenerative diseases are associated with the abnormal accumulation of protein aggregates in the neurons of affected individuals. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal human neurodegenerative disease caused primarily by a loss of motor neurons. Recently, mutations in a gene called fused in sarcoma (FUS) were identified in some ALS patients. The basic mechanisms by which FUS contributes to ALS are unknown. We have addressed this question using protein biochemistry and the genetically tractable yeast Saccharomyces cerevisiae. We defined the regions of biochemically pure FUS protein that contribute to its aggregation and toxic properties. We then used genome-wide screens in yeast to identify genes and cellular pathways involved in the toxicity of FUS. Many of the FUS toxicity modifier genes that we identified in yeast have clear homologs in humans, suggesting that these might also be relevant for the human disease. Together, our studies provide novel insight into the basic mechanisms associated with FUS aggregation and toxicity. Moreover, our findings open new avenues that could be explored for therapeutic intervention.

Highlights

Amyotrophic lateral sclerosis (ALS), called Lou Gehrig’s disease, is a devastating neurodegenerative disease
Mutations in a gene called fused in sarcoma (FUS) were identified in some ALS patients
The basic mechanisms by which FUS contributes to ALS are unknown. We have addressed this question using protein biochemistry and the genetically tractable yeast Saccharomyces cerevisiae

Summary

Introduction

Amyotrophic lateral sclerosis (ALS), called Lou Gehrig’s disease, is a devastating neurodegenerative disease It is a rapidly progressing motor neuron wasting disorder that leads to paralysis and death typically within 2–5 years of onset. Wild-type (WT) TDP-43 accumulates abnormally in cytoplasmic, ubiquitinated inclusions in degenerating neurons of ALS and FTLD-TDP patients, and mutations in the TDP-43 gene are linked with disease in rare familial and sporadic cases. Despite these advances, how TDP-43 contributes to disease, which domain of TDP-43 drives aggregation, and how ALS-linked mutations affect TDP-43 function and aggregation remained unclear

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