My laboratory is interested in exploring how neurons die in neurodegenerative disorders and stroke, with a specific focus on how abnormally folded proteins, such as amyloid b-peptide and polyglutamine-containing proteins, cause neuronal death. These proteins are involved in the pathogenesis of Alzheimer’s disease and several dominantly inherited neurologic diseases, such as Huntington’s disease, dentatopallidoluysian atrophy and several spinocerebellar ataxias.
We initially focused on the ability of heat shock proteins or molecular chaperones to alter neuronal vulnerability to injury. More recently, we have examined the role of the proteasomal protein degradation system in neuronal injury. Most of our studies are done in primary neuronal cell culture, with an additional focus on neurons derived from murine embryonic stem cells.
Recently, we and others observed that neurons (and other cell types) can increase the function of the proteasomal protein degradation system in response to proteasome inhibition or oxidative stress. We are very interested in understanding how proteasome function is increased, and developing strategies to increase proteasome function as a potential therapeutic modality.
We are also interested in the mechanisms of neuronal death following proteasome inhibition or other injuries. Unlike neuronal death caused by over-stimulation of NMDA receptors (excitotoxic neuronal death), the neuronal death caused by inhibition of proteasome function is associated with a reduction, rather than an increase, in intracellular calcium levels ([Ca2+]i). If, as some studies suggest, proteasome function is impaired in the brains of patients with dementing disorders, these findings would suggest that treatments that reduce neuronal [Ca2+]i might exacerbate rather than reduce neuronal loss.