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''RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. '''Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction.''' Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.'' {{#pmid:26385636|Coyne2015}}
 
''RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. '''Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction.''' Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.'' {{#pmid:26385636|Coyne2015}}
  
''DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. '''Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43.''' Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.'' {{#pmid:26130692|Chou2015}}
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''DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.'' {{#pmid:26130692|Chou2015}}
  
 
''Certainly, small molecule activators of the UPS or autophagy have been shown to promote TDP-43 clearance and/or mitigate toxicity in models based on TDP-43 overexpression [66, 77, 98, 99]. Autophagy activators may offer selectivity in clearing misfolded TDP-43 [76, 79]; however, given the ability of TDP-43 to autoregulate, even nonselective clearance strategies hold promise for safely restoring TDP-43 proteostasis. [...] '''There are several intrinsic cellular mechanisms that can act to either prevent or resolve protein misfolding, namely the chaperone system, autophagy, and the UPS.''' The chaperone system maintains proper protein folding during synthesis and thereafter, or delivers misfolded substrates for degradation [161]. '''In the case of TDP-43, the chaperone heat shock protein (Hsp)90 enhances solubility (i.e., folding) [162], while [[HspB8]] promotes autophagic clearance of aggregated TDP-43 [163]. Potentiated forms of the disaggregase [[Hsp104]] can mediate TDP-43 refolding [161].''' Monomeric misfolded TDP-43 is likely handled by the UPS [76]'' {{#pmid:25652699|Scotter2015}}
 
''Certainly, small molecule activators of the UPS or autophagy have been shown to promote TDP-43 clearance and/or mitigate toxicity in models based on TDP-43 overexpression [66, 77, 98, 99]. Autophagy activators may offer selectivity in clearing misfolded TDP-43 [76, 79]; however, given the ability of TDP-43 to autoregulate, even nonselective clearance strategies hold promise for safely restoring TDP-43 proteostasis. [...] '''There are several intrinsic cellular mechanisms that can act to either prevent or resolve protein misfolding, namely the chaperone system, autophagy, and the UPS.''' The chaperone system maintains proper protein folding during synthesis and thereafter, or delivers misfolded substrates for degradation [161]. '''In the case of TDP-43, the chaperone heat shock protein (Hsp)90 enhances solubility (i.e., folding) [162], while [[HspB8]] promotes autophagic clearance of aggregated TDP-43 [163]. Potentiated forms of the disaggregase [[Hsp104]] can mediate TDP-43 refolding [161].''' Monomeric misfolded TDP-43 is likely handled by the UPS [76]'' {{#pmid:25652699|Scotter2015}}

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