The neuroprotective potential of endoplasmic reticulum chaperones.

Diseases of the nervous system are characterized by axon dysfunction, axon degeneration, and neuronal cell death. The roster of neurodegenerative diseases is striking in the selective vulnerability of the affected neuronal populations and the timing of the onset of disease manifestation and functional deficits. We are particularly fascinated by the extreme long term progression of many of these diseases prior to onset of significant functional loss and believe this reveals essential qualities of these diseases and offers considerable therapeutic opportunity. Though a complete mechanistic understanding of axon maintenance and neurodegeneration remains elusive, the primary process of neurodegeneration appears similar (e.g., Wallerian degeneration) across neuronal populations, as does caspase-dependent or -independent apoptotic cell death and likewise other forms of cell death (e.g., necrosis and necroptosis). Thus, it seems probable that the basic mechanisms of neuronal cell death and degeneration can be selectively manipulated through core cell processes, thereby preventing and/or halting the disease onset and progression.