Dissecting the molecular basis of neurodegeneration in Cockayne syndrome

Cockayne syndrome (CS) is a progressive developmental and neurodegenerative disorder, associated with a DNA repair defect, resulting in premature death during childhood. There is currently no cure for CS and treatment is directed at alleviating symptoms. Most of patients are mutated in the csb gene. Even if the genetic basis of this disorder have been identified, the molecular neuropathology associated with such deficit is largely unknown. Observation that neurological symptoms may be detected either at birth or during the childhood suggests a key role for CSB protein in the plasticity and the maintenance of central nervous system. We have previously found that the CSB defect results, in fibroblasts, in altered expression of pro-apoptotic proteins and enhanced programmed cell death, after many kind of stress, including oxidative attack and hypoxia. A likely possibility is that the loss of CSB gives rise to a massive death of neural cells thereby affecting the homeostasis of nervous system tissues. Alternatively, CSB deficiency might impact the transcriptional programs that govern survival and differentiation of adult neural stem cells. We will determine the specific sites of programmed cell death and whether neuron cell loss is a primary event or due to loss of progenitor/stem cells or associated cell types. Further, we will analyze to what extension the impaired capability of CS-B cells to adequately respond to oxidative attack and hypoxia affects the integrity and differentiation capabilities of adult neural stem/progenitor cells as well as the viability of their differentiated cell lineages (neurons, astrocytes, oligodendrocytes and Schwann cells). Our innovative approach makes use of either primary or immortalized neural progenitor cell systems with efficient self-renewal and multi-lineage differentiation capabilities or differentiated neural cell types such as neurons, oligodendrocytes, astrocytes and Schwann cells which would likely provide valuable information on the molecular cause of neurodegeneration in CS-B patients. Successful conclusion of these studies will expand our knowledge of mechanisms of neurodegeneration and lay the groundwork for development of therapeutic approaches for CS patients.