Identification and characterization of a dynactin associated protein (Dynapsin) involved in late-onset Alzheimer disease (AD). J.R. Gilbert¹, S. Zuchner¹, C.A. Browning¹, G.F. Wang¹, C.R. Lu¹, P.G. Bronson¹, C.F. Potocky¹, S.M. Garvey¹, C.C. Kroner¹, J.R. Gibson¹, J.M. van der Walt¹, Y.J. Li¹, P.T. Xu¹, D.E. Schmechel¹, W.K. Scott¹, J.M. Vance¹, J.L. Haines², E.R. Martin¹, M.A. Pericak-Vance¹. 1) Duke University, Durham, NC; 2) Vanderbilty University, Nashville, TN.
   To date four genes, PS1, PS2, APP and APOE have been shown to be involved in the etiology of AD. Using ordered subset analysis (OSA) we established linkage (MAXLOD=3.8) on chromosome 2q33.3 in 31 multiplex AD families with >1 individual with age at onset of AD between 50-60 years. To prioritize candidate genes in the linkage region, we used genomic convergence integrating our linkage data with SAGE expression analysis derived from AD hippocampus. One novel gene, dynapsin was identified. Genotyping a dense array of SNPs across the linkage region further supported the involvement of dynapsin in AD with significant evidence for association in multiple SNPs (minimum p=0.008) in the gene. The association was strengthened when the sample size was increased to a total of 73 AD pedigrees meeting the OSA criteria for chromosome 2 (minimum p=0.003). Little is known about dynapsin or its functional role in the CNS. We identified up to 8 different cDNA isoforms and analyzed their relative expression levels in AD and control brains. Isoform 7 was more highly expressed and variable in AD brains versus controls. In AD brain sections, dynapsin is found in neurons and importantly, in AD neuritic plaques. We also demonstrated that dynapsin immunoprecipitates with components of the dynein-dynactin motor complex and was localized to cytoplasmic vesicles in a cell culture of Neuro2A cells. We hypothesize that dynapsin is a newly identified linker protein between vesicles and the dynein-dynactin complex and is involved in endosomal trafficking. Axonal transport and synaptic integrity are key elements of the proposed pathways for AD. Our combined genetic, molecular and functional results strongly suggest a role for dynapsin in the etiology of AD and that variation in dynapsin is responsible for at least some of the risk of developing AD in these families.