Molecular chaperone models and neurodegeneration

As we age nerve cells in the brain can start to malfunction and die leading to dementia and other diseases. This process is associated with clumps of aggregated proteins. Cells have molecular machines made of chaperone proteins that can stop protein aggregation. We are testing if a special nerve cell chaperone is involved in these processes in the brain and if we can manipulate this chaperone to affect the development or effects of the aggregates. This research could highlight this special chaperone as a potential new target for the development of treatments for several forms of dementia and neurodegeneration, such as Alzheimer’s, Parkinson’s, Huntington’s and Motor neuron disease.

Protein folding and quality control are facilitated by molecular chaperones and aberrant protein folding is associated with many forms of neurodegeneration. The neuronal proteins HSJ1a and HSJ1b are unique mammalian chaperones. They combine a J domain that regulates Hsp70, a novel substrate binding domain and two ubiquitin interacting motifs (UIMs). This combination of motifs enables HSJ1 proteins to sort misfolded proteins for proteasomal degradation. We have shown that HSJ1 proteins are neuroprotective against polyglutamine mediated neurodegeneration. HSJ1a suppressed polyglutamine aggregation dependent on correct subcellular targeting, a functional J domain and the UIMs, whereas HSJ1b did not affect polyglutamine aggregation but still enhanced neuronal survival associated with a stimulation of BDNF release. These data suggest that both HSJ1 proteins could be important modulators of neurodegeneration. With the support of an MRC Pathfinder we have generated transgenic lines which overexpress HSJ1a or HSJ1b and a conditional animal model which lacks both HSJ1 proteins. This proposal aims to study the effect of manipulating HSJ1 expression on neuronal development, function, stress tolerance and neurodegeneration. These HSJ1 transgenic mice will be crossed with a range of animal models of neurodegeneration to test if the overexpression of either isoform can protect against neurodegeneration or if the absence of HSJ1 exacerbates neurodegeneration in these models. We will also delineate the mechanisms of HSJ1 mediated neuroprotection and test if HSJ1 proteins are involved in the neuroprotective action of certain drugs. These studies will address an important question relating to the role of molecular chaperones in the nervous system and importantly they will also enhance our understanding of their role in neurodegeneration which could have potential therapeutic applications.