Accumulation of the microtubule associated protein tau is associated with neuronal death in Alzheimer's disease (AD), Parkinson's disease and traumatic brain injury (TBI). Therefore tau is a tractable therapeutic target for each of these diseases. The chaperone family of proteins, and in particular the heat shock protein 70 family, is critical for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is strongly associated with granulovacuolar degenerating bodies (GVDs), which are major tau-associated pathological entities in AD neurons that are linked to autophagic clearance mechanisms. Co-localization studies have also shown that Hsp73 associates with accumulated tau in the brain. However, the actual mechanisms involving the Hsp70 family with tau biology have been challenging to define. Hsp70 proteins can either promote tau clearance or functionally preserve it. Recently, we have begun to elucidate the reason for this dichotomy. We have found that Hsp70 proteins act to seek out, identify and hold onto tau, but other chaperones termed DnaJ proteins by manipulating substrate selection and Hsp70 ATPase activity dictate whether this Hsp70-bound tau should be preserved, sequestered or destroyed. Therefore, we will test the hypothesis that regulation of tau triage by Hsp70 proteins is mediated through the Hsp70/DnaJ interface by: 1) determining whether chemical modulation of the DnaJ- binding domain on Hsp70 proteins regulates tau stability in vivo;2) determining whether genetic modulation of the DnaJ-binding domain on Hsp73 regulates tau stability in vivo;and 3) determining whether modulating discreet DnaJ proteins directly can regulate tau processing in vivo. Successful completion of these studies will prove the relevance of the DnaJ/Hsp70 interface as a possible treatment for AD, PD, TBI and more than 15 other neurodegenerative diseases termed tauopathies.
The tau protein accumulates in more than 15 neurodegenerative diseases collectively termed tauopathies, the most common being Alzheimer's disease. Despite this fact, only one drug is currently in clinical trials that targets the tau protein. This is largely due to our lack of understanding of how the brain deals with tau under normal circumstances. Here, we have developed new ways to manipulate the protein, Hsp70, a central regulator of tau fate, to either preserve or remove tau from the brain. These strategies will yield novel therapeutic strategies to treat Alzheimer's, Parkinson's and traumatic brain injury. These studies may lead to drug development that can provide veterans suffering from AD, PD and TBI a way to combat their condition, with the ultimate goal being a cure.
|Baker, Jeremy D; Shelton, Lindsey B; Zheng, Dali et al. (2017) Human cyclophilin 40 unravels neurotoxic amyloids. PLoS Biol 15:e2001336|
|Shelton, Lindsey B; Baker, Jeremy D; Zheng, Dali et al. (2017) Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A 114:9707-9712|
|Martin, Mackenzie D; Baker, Jeremy D; Suntharalingam, Amirthaa et al. (2016) Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules. ACS Chem Biol 11:2041-8|
|Fontaine, Sarah N; Zheng, Dali; Sabbagh, Jonathan J et al. (2016) DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J 35:1537-49|
|Sabbagh, Jonathan J; Fontaine, Sarah N; Shelton, Lindsey B et al. (2016) Noncontact Rotational Head Injury Produces Transient Cognitive Deficits but Lasting Neuropathological Changes. J Neurotrauma 33:1751-1760|
|Martin, Mackenzie D; Calcul, Laurent; Smith, Courtney et al. (2015) Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance. ACS Chem Biol 10:1099-109|
|Blair, Laura J; Frauen, Haley D; Zhang, Bo et al. (2015) Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol Commun 3:8|
|Fontaine, Sarah N; Sabbagh, Jonathan J; Baker, Jeremy et al. (2015) Cellular factors modulating the mechanism of tau protein aggregation. Cell Mol Life Sci 72:1863-79|
|Fontaine, Sarah N; Martin, Mackenzie D; Akoury, Elias et al. (2015) The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics. Hum Mol Genet 24:3971-81|
|Fontaine, Sarah N; Rauch, Jennifer N; Nordhues, Bryce A et al. (2015) Isoform-selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement. J Biol Chem 290:13115-27|
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