Tae-Wan Kim, Ph.D.

Molecular and Physiological Analysis of Presenilin Function in Familial Alzheimer’s Disease

Our current research is aimed at elucidating the molecular mechanisms underlying familial Alzheimer’s disease (FAD). A significant portion of AD is caused by the inheritance of certain defective genes. Mutations in the genes encoding the presenilins (PS1 and PS2) cause the majority of early-onset cases of familial AD (FAD). The central focus of my research is to define the precise molecular steps by which defects in presenilin genes lead to the characteristic pathogenesis and molecular phenotypes associated with FAD. An in-depth understanding of how mutations in the presenilins lead to beta-amyloid deposition, neuronal cell death, and dementia will be invaluable for the development of novel therapies for AD.

Our on-going projects are:

1. Role of Presenilins in Store-Operated Calcium Entry and Intramembrane Proteolysis (gamma-Secretase Activity)
2. RNAi-based Phenotypic Analysis of Presenilin Function
3. Proteomic Analysis to Identify Novel Substrates for Presenilin-dependent gamma-Secretase

Selected Publications:

• Kim T-W, Pettingell WH, Hallmark OG, Moir RD, Wasco W, Tanzi RE. Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J. Biol. Chem., 272: 11006-11010 (1997).

• Kim T-W, Tanzi RE. Presenilins and Alzheimer's disease. Curr. Opin. Neurobiol. 7: 683-688 (1997).

• Kim T-W, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science, 277: 373-376 (1997).

• Kim T-W, Tanzi RE. Neuronal intranuclear inclusions in polyglutamine diseases: nuclear weapons or nuclear fallout? Neuron, 21: 657-659 (1998).

• Saunders AJ, Kim T-W, Tanzi RE. BACE maps to chromosome 11 and a BACE homologue, BACE2, resides in the obligate Down's syndrome region of chromosome 21. Science, 286: 1255-56a. (1999).

• Pack-Chung E, Meyers M, Pettingell WP, Moir RD, Brownawell AM, Cheng I, Tanzi RE and Kim T-W. Presenilin 2 interacts with Sorcin, a modulator of the ryanodine receptor. J. Biol. Chem., 275: 14440-14445 (2000).

• Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, and Kim T-W. Presenilin-mediated modulation of capacitative calcium entry. Neuron, 27: 561-572 (2000).