ABSTRACT
Mutations in Fused in Sarcoma (FUS) are present in familial and sporadic cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS is localised in the nucleus where it has important functions in DNA repair. However, in ALS/FTD, mutant FUS mislocalises from the nucleus to the cytoplasm where it forms inclusions, a key pathological hallmark of neurodegeneration. Mutant FUS also inhibits protein import into the nucleus, resulting in defects in nucleocytoplasmic transport. Fragmentation of the neuronal Golgi apparatus, induction of endoplasmic reticulum (ER) stress, and inhibition of ER-Golgi trafficking are also associated with mutant FUS misfolding in ALS. Protein disulphide isomerase (PDI) is an ER chaperone previously shown to be protective against misfolding associated with mutant superoxide dismutase 1 (SOD1) and TAR DNA-binding protein-43 (TDP-43) in cellular and zebrafish models. However, a protective role against mutant FUS in ALS has not been previously described. In this study, we demonstrate that PDI is protective against mutant FUS. In neuronal cell line and primary cultures, PDI restores defects in nuclear import, prevents the formation of mutant FUS inclusions, inhibits Golgi fragmentation, ER stress, ER-Golgi transport defects, and apoptosis. These findings imply that PDI is a new therapeutic target in FUS-associated ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Endoplasmic Reticulum Stress , Frontotemporal Dementia/drug therapy , Mutation , Procollagen-Proline Dioxygenase/pharmacology , Protein Disulfide-Isomerases/pharmacology , RNA-Binding Protein FUS/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Cell Line , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Humans , In Vitro Techniques , Models, Theoretical , Protein FoldingABSTRACT
Rab GTPases are becoming increasingly implicated in neurodegenerative disorders, although their role in amyotrophic lateral sclerosis (ALS) has been somewhat overlooked. However, dysfunction of intracellular transport is gaining increasing attention as a pathogenic mechanism in ALS. Many previous studies have focused axonal trafficking, and the extreme length of axons in motor neurons may contribute to their unique susceptibility in this disorder. In contrast, the role of transport defects within the cell body has been relatively neglected. Similarly, whilst Rab GTPases control all intracellular membrane trafficking events, their role in ALS is poorly understood. Emerging evidence now highlights this family of proteins in ALS, particularly the discovery that C9orf72 functions in intra transport in conjunction with several Rab GTPases. Here, we summarize recent updates on cellular transport defects in ALS, with a focus on Rab GTPases and how their dysfunction may specifically target neurons and contribute to pathophysiology. We discuss the molecular mechanisms associated with dysfunction of Rab proteins in ALS. Finally, we also discuss dysfunction in other modes of transport recently implicated in ALS, including nucleocytoplasmic transport and the ER-mitochondrial contact regions (MAM compartment), and speculate whether these may also involve Rab GTPases.
