42 research outputs found
Hsp40 Couples with the CSPĪ± Chaperone Complex upon Induction of the Heat Shock Response
In response to a conditioning stress, the expression of a set of molecular chaperones called heat shock proteins is increased. In neurons, stress-induced and constitutively expressed molecular chaperones protect against damage induced by ischemia and neurodegenerative diseases, however the molecular basis of this protection is not known. Here we have investigated the crosstalk between stress-induced chaperones and cysteine string protein (CSPĪ±). CSPĪ± is a constitutively expressed synaptic vesicle protein bearing a J domain and a cysteine rich āstringā region that has been implicated in the long term functional integrity of synaptic transmission and the defense against neurodegeneration. We have shown previously that the CSPĪ± chaperone complex increases isoproterenol-mediated signaling by stimulating GDP/GTP exchange of GĪ±s. In this report we demonstrate that in response to heat shock or treatment with the Hsp90 inhibitor geldanamycin, the J protein Hsp40 becomes a major component of the CSPĪ± complex. Association of Hsp40 with CSPĪ± decreases CSPĪ±-CSPĪ± dimerization and enhances the CSPĪ±-induced increase in steady state GTP hydrolysis of GĪ±s. This newly identified CSPĪ±-Hsp40 association reveals a previously undescribed coupling of J proteins. In view of the crucial importance of stress-induced chaperones in the protection against cell death, our data attribute a role for Hsp40 crosstalk with CSPĪ± in neuroprotection
Genes of susceptibility to early neurodegenerative changes in the rat retina and brain: analysis by means of congenic strains
Improving collection efforts to avoid loss of biodiversity: lessons from comprehensive sampling of lycophytes and ferns in the subtropical Atlantic Forest
Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation
A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ā¼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-Ī² and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3Ī² is strongly upregulated due to TDP-43 expression, and reduced GSK-3Ī² dosage is also a common suppressor of AĪ²42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation