FUS Interacts with HSP60 to Promote Mitochondrial Damage

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.

A new method for quantifying mitochondrial axonal transport

“…Our recent work has shown that fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS), a nuclear RNA binding protein, interacts with and targets mitochondria (Deng et al, 2015). This prompted us to carefully examine effects of wild-type and ALS-mutant FUS on axonal mitochondrial transport.…”

“…To further examine FUS activity in vivo , we used our previously established fly model for FUS proteinopathy (Chen et al, 2011; Deng et al, 2015). We crossed mitoGFP into the transgenic flies expressing human Wt- or P525L-mutant FUS to track mitochondrial movement in motor neuron axons of these transgenic flies.…”

“…These data are consistent with that obtained from cultured mammalian neurons, both supporting that increased FUS expression reduces axonal mitochondrial transport. Previous studies have shown increased FUS expression in patients affected by frontotemporal lobar degeneration associated with FUS (FTLD-FUS) (Mackenzie et al, 2011; Sabatelli et al, 2013; Deng et al, 2015). Consistently, transgenic animals overexpressing the human FUS protein recapitulate critical pathological and clinical features of FUS proteinopathy (e.g, Huang et al, 2011; Chen et al, 2011; Lanson et al, 2011).…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…On the contrary, other chaperones such as HSP70/Hsc70, cyclophilin-A, aB-crystallin and glutathione peroxidase have no effect in blocking SOD1 misplacing onto the mitochondrial outer membrane which consequently, leads to damaged mitochondrial integrity [176]. Recently, reduced expression of HSP60 has exhibited the protective role against mitochondrial damage in ALS because interaction between mitochondrial chaperonin, HSP60 and FUS protein causes its translocation to mitochondria and leads to cell damage [177]. Further, it has been reported that small HSPs, including the HSP27, HSP25 and α-crystallin family also impart neuroprotective and cardioprotective effect against secondary complications of T2D [178].…”

A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway

“…And RNA binding proteins could be potential targets in prostate cancer [13]. RNA binding protein FUS has been shown to interact with HSP60 (Heat Shock Protein Family 60) to promote mitochondrial damage [14]. FUS-CHOP promotes invasion in myxoid liposarcoma through a SRC (SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase)/FAK (Focal Adhesion Kinase)/RHO (Rhodopsin)/ROCK (Rho Associated Coiled-Coil Containing Protein Kinase)-dependent pathway [15].…”