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Vincenzo A. Gennarino, Ph.D.
Protein Dosage and Neurological Disorders
Postdoctoral Associate, Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine
2 Riverside Circle, Roanoke, VA 24016
The family of neurodegenerative disorders known as proteinopathies, the most well known of which are Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, involve problems with protein folding and clearance. In most cases, a mutation alters the conformation of the disease-causing protein in a way that changes its function, and it causes the protein to accumulate in the neurons over time. Recent work has provided evidence that even wild-type proteins can wreak havoc when they are expressed at high levels. For example, duplication of the amyloid precursor protein (APP) locus causes autosomal dominant early-onset Alzheimer’s disease, and duplications or triplications of α-synuclein (SNCA) are associated with familial Parkinson’s disease. In animal models, extremely high (30x-40x) levels of wild-type ataxin1 (Atxn1) cause disease reminiscent of spinocerebellar ataxia type 1 (SCA1). This raises the question: could less extreme elevations of these protein levels still cause disease? In particular, could aberrant RNA processing and post-transcriptional regulation of specific proteins alter their steady-state levels sufficiently to cause neurodegeneration? The coordinated activities of microRNA (miRNA) and RNA-binding proteins (RBPs) regulate mRNA turnover, localization and translation, and orchestrate hundreds of circuits that are responsible for proper cognitive function. Yet, little is known about the role of miRNA and RBPs in brain development or disease. Dr. Gennarino will discuss how he has pursued this line of thought by investigating the regulation of two proteins involved in neurological disease: ATXN1, whose mutant form causes the adult-onset neurodegenerative disease SCA1, and MeCP2, whose mutation causes the postnatal neurodevelopmental disorder Rett syndrome.