Abstract
FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons
Depending on the regions affected, FUS-proteinopathies can manifest as motor neuron disease such as ALS-FUS, or as various forms of dementia including frontotemporal lobar degeneration with FUS pathology (FTLD-FUS),atypical FTLD with ubiquitin pathology, neuronal intermediate filament inclusion disease (NIFID), and Basophilic Inclusion Body Disease (BIBD) [4,10,11,12,13,14]
Because no FUS mutation has been detected in most FTLD-FUS patients and because the patient samples that we examined showed elevated FUS protein levels, the work in this study examining the effects of increased Wt-FUS expression is pertinent to understanding FTLD-FUS, whereas the data with ALS-mutant FUS, such as P525L, is relevant to ALS-FUS
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons. Genetic studies have uncovered more than ten ALS-associated genes [3,4,5] Among these are genes encoding RNA/DNA binding proteins, including TAR-DNA binding protein of 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) [6,7,8,9]. FUS immunoreactive inclusion bodies are detected in a range of neurological diseases classified as FUS-proteinopathies. These disorders are genetically and clinically heterogeneous. A recent study has identified several mutations in the 3’ untranslated region of the FUS gene that are associated with increased FUS expression among ALS patients [16], suggesting that increased FUS expression could be a mechanism contributing to the pathogenesis of ALS
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