Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes

Neurobiology of Disease

Winfried Edelmann¹  Marcy E. MacDonald²  Audrey Hendricks²  Kathryn L. Lunetta³  Errol C. Friedberg⁴  Raju Kucherlapati⁵  Ella Dragileva⁶  Edith T. Lopez⁶  Allison Teed⁶  Vanessa C. Wheeler⁶  Tammy Gillis⁶ 

[1] Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA;Department of Biostatistics, Boston University School of Public Health, Boston MA 02118, USA;Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NJ 10461, USA;Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA;Harvard Partners Center for Genetics and Genomics, 65 Landsdowne Street, Cambridge, MA 02139, USA;Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA;

关键词: Huntington's disease;    Trinucleotide;    Instability;    Repeat;    Striatum;    Repair;   

DOI  :  

来源: DOAJ

【 摘 要 】

Modifying the length of the Huntington's disease (HD) CAG repeat, the major determinant of age of disease onset, is an attractive therapeutic approach. To explore this we are investigating mechanisms of intergenerational and somatic HD CAG repeat instability. Here, we have crossed HD CAG knock-in mice onto backgrounds deficient in mismatch repair genes, Msh3 and Msh6, to discern the effects on CAG repeat size and disease pathogenesis. We find that different mechanisms predominate in inherited and somatic instability, with Msh6 protecting against intergenerational contractions and Msh3 required both for increasing CAG length and for enhancing an early disease phenotype in striatum. Therefore, attempts to decrease inherited repeat size may entail a full understanding of Msh6 complexes, while attempts to block the age-dependent increases in CAG size in striatal neurons and to slow the disease process will require a full elucidation of Msh3 complexes and their function in CAG repeat instability.

【 授权许可】

Unknown