Dr. Yoshinori Kohwi

Life Sciences Division, Lawrence Berkeley National Laboratory

All living things have materials inherited from predecessors. The material behind genetic inheritance is DNA, which is a long string of nucleotide units attached to one another. One nucleotide unit is composed of three groups, phosphate group, sugar group and nitrogenous base. The nitrogenous bases make DNA variable. There are 4 different bases, cytosine (C), adenine (A), guanine (G) and thymine (T). It is the variability of these bases that constitutes the genetic code. Every human being has mutations in the DNA, the location differing from person to person. Mutations occurring in a particular gene may sometimes be fatal or may cause a particular hereditary disease.

Huntington's Disease (HD) was found to include an expansion mutation of a simple trinucleotide repeat, CAG repeat, in the causal gene. So far, similar trinucleotide repeat expansions, CAG repeats and CGG repeats, have been discovered in 16 different genes which cause hereditary neurological diseases. Research in this past decade, both basic and clinical, has given us a much better understanding of these diseases; however, we still do not know why such a simple mutation occurs in different genes nor why it leads to a variety of different neuronal dysfunctions in different regions of the brain.

Dr. Kohwi's laboratory focuses on the biological role of neuronal mRNA binding proteins in Huntington Disease (HD) pathogenesis. The group of disorders that includes HD, spinal bulbar muscular atrophy (SBMA) and spinocerebellar ataxia (SCA) is characterized phenotypically by progressive neuronal degeneration. The coding regions of the responsible genes of the diseases are marked by the expansion of (CAG) repeats, giving rise to expanded (CAG)-repeat in the mRNA and polyglutamine tracts in the proteins. In general, the length of the repeat in the gene is inversely related to the age of onset of the disease; the longer the repeat, the earlier the onset of the disease. Each pathologic protein is widely expressed, but the neuronal degeneration occurs at the specific regions within the central nervous system in each disorder. Our laboratory previously identified neuronal mRNA binding proteins that bind a selected group of mRNAs in vivo, including the mRNA of mutant huntingtin in HD model mice. The neuronal mRNA binding proteins may be important in proper localization and translational regulation of mRNAs in neurons. It is the goal of our laboratory to understand how the alteration of mRNA localization and translation triggers neuronal dysfunction resulting in age-dependent neuronal disorders, using HD as a model system.