Sporadic neurodegenerative disorders are prevalent in the aging population, yet their origins remain difficult to explain and treatment regimens often of limited effectiveness. Though tremendous diversity exists in the specific cell types or regions of the CNS affected between these diseases, they are linked by a common characteristic: the formation of protein aggregates in or surrounding dying cells. Insights gleaned from the study of loss of function mutations that predictably confer the formation of protein aggregates in neurons and subsequent neuron death, allow us to uncover proteostatic pathways essential for neuron survival that may be disrupted in both sporadic and familial forms of human neurodegenerative disorders. Our lab uses a forward genetic approach to identify homeostatic pathways critical to neuron function and survival. Recently we discovered a spontaneous mutation in mice that leads to the formation of protein aggregates followed by progressive loss of cerebellar Purkinje cells and ataxia beginning at 1 month of age in mice that are homozygous for this mutation. By positional cloning, we identified a mutation in the Rreb1 zinc finger transcription factor that co-segregates with aggregate formation, neuron loss, and ataxia. Interestingly, heterozygosity for this mutation is also associated with Purkinje cell loss, although the onset of neuron death is later and less severe, suggesting that loss of Rreb1 function and neuron survival are tightly linked at the dosage level. Few transcription factors have been associated with loss of neuronal proteostasis with most studies focused on the production and/or clearance of misfolded proteins caused by dominant mutations in genes encoding these proteins. Though little is known about the role of Rreb1 in the nervous system, several studies have focused on the role of this protein in regulating transcription in development, citing its ability to bind directly to DNA via several zinc finger domains and recruit histone deacetylases, histone demethylases, and co-repressor complexes to remodel chromatin and ultimately control gene expression. Using this novel model of neurodegeneration, I will investigate the role of Rreb1 in neurons and determine how the disruption of this gene leads to an imbalance in proteostasis and ultimately neuron cell death.
A common feature of many neurodegenerative diseases is the formation of protein aggregates, highlighting the fundamental importance of proteostasis in neuron health and survival. Here, I propose to identify a novel role for a transcription factor, RREB1, as a regulator of proteostasis which, upon disruption, gives rise to aggregate formation and neuron death. This proposed study will shed light on the molecular pathways integral to the maintenance of a healthy cellular proteome and the long-term survival of neurons.
