Albert R. La Spada, MD, PhD
In my laboratory, we apply the tools of molecular genetics, neuroscience, and functional genomics to understand the mechanisms of neurodegenerative disease. Within the last decade, it has become clear that a key question in the neurodegenerative disease field is the selective vulnerability of different neuronal populations in the various diseases. Inherited disorders such as Huntington's disease are characterized by widespread expression of a mutant gene product throughout the central nervous system but display well circumscribed patterns of neuronal dysfunction and demise. This theme is also apparent in genetic examples of common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and prion disease. My lab studies the molecular basis of the CAG / polyglutamine repeat diseases of which there are nine: Huntington's disease, X-linked spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and six forms of spinocerebellar ataxia. As the patterns of expression of the different disease genes are widespread throughout the neuraxis, the CAG / polyglutamine diseases represent an excellent example of neuronal selectivity. Thus, insights into the basis of selective neurodegeneration in these disorders may be relevant to understanding this phenomenon in a wide range of neurological disease processes. We have found that transcription dysregulation and activation of apoptosis – autophagy are important pathways in these diseases. In other studies, we have learned that protease function and proteolytic cleavage may be important. Our goal is to delineate the molecular and cellular pathways by which neurons become dysfunctional and use this knowledge to devise rationale therapies for this class of diseases.