NAF Ataxia Research Studies Currently Underway

Michael D Herbert, PhD

The University of Mississippi Medical Center
PolyQ proteins and pre-mRNA splicing

Summary: Studies of nuclear organization and function have revealed that the nucleus contains a myriad of dynamic, highly organized domains, territories and bodies. Various diseases are characterized by the disruption of these structures or alteration in their protein composition. For example, most patients with the neurodegenerative disorder Spinal Muscular Atrophy have a mutation that prevents a crucial protein from localizing to a specific nuclear domain called the Cajal body (CB). In the group of polyglutamine (polyQ) neurodegenerative diseases, the mutant proteins form distinctive nuclear inclusions that may affect the function of the CB. Current evidence implicates the CB as the site for the maturation of factors necessary for proper RNA processing. The mutant proteins that cause spinocerebellar ataxia 1 or Huntington's disease do not form nuclear inclusions which dramatically alter CB localization. In contrast, mutant ataxin-3 (which causes Machado-Joseph disease) forms inclusions that tether CBs. We therefore hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect the maturation of factors required for RNA processing. The experiments proposed in this application should greatly clarify our understanding into how polyQ diseases affect the functional organization of the nucleus. These studies will also provide a rationale for exploring if patient samples have reduced pre-mRNA splicing. With such knowledge, we will be able to ascertain if alterations in RNA processing account for neuronal demise in both polyQ disorders as well as other neurodegenerative diseases such as Spinal Muscular Atrophy. Consequently, therapies designed to increase splicing may be beneficial to patients that suffer from these insidious diseases.