PRIMARY FACULTY MEMBER
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Seong-Hun Kim, Ph.D. Asst. Professor Phone: 352-392-5311 Office: R5-250 Academic Research Bldg. Email: skim09@ufl.edu Publications: Search PubMed |
Research Interests
Research efforts in our laboratory have been focused on elucidating the molecular and cellular mechanisms involved in the pathogenesis of Alzheimer's disease (AD), the most common cause of dementia in adults. The key pathogenic player is ~4kD amyloid β peptides (Aβ ), which are derived from a larger precursor protein (β-amyloid precursor protein (APP)) by the concerted action of two proteolytic enzymes termed “ β-secretase” (BACE1) and “γ-secretase” (a macromolecular complex containing presenilins (PS1 or PS2) at its catalytic core). Normally, the 40-amino acid form of Aβ (Aβ40) accounts for ~90% of Aβ secreted from cells, but the longer, 42-residue form (Aβ42) are more prone to aggregation and deposited early and selectively in the brains of AD patients. Genetic studies of early-onset familial AD (FAD) cases revealed causative mutations in the genes encoding either the precursor protein (APP) or the protease (PS1 and PS2), supporting the critical role of Aβ in the pathogenesis of AD. Interestingly, all the FAD-associated mutations identified so far , by unknown mechanism(s), increased the ratio of Aβ42/Aβ40. Since oligomeric Aβ is believed to trigger a cascade of events that lead to neuronal dysfunction and cognitive decline, inhibition of γ-secretase could be attractive strategies to prevent and treat AD.
γ-Secretase is a unique enzyme in that it cleaves its substrates within hydrophobic lipid bilayers that normally exclude water. More than 30 substrates have now been identified for γ-secretase including APP and Notch. Four essential core components of the γ-secretase complex have been identified; presenilins (PS1 or PS2), nicastrin (NCT), APH-1 and PEN-2. During the assembly, APH-1 and NCT first form a stable subcomplex that binds to PS1 and the APH-1/NCT/PS1 complex then associates with PEN-2 which promotes the endoproteolysis of PS1, an essential step for γ-secretase maturation. Active γ-secretase complex is assembled in the endoplasmic reticulum (ER) but only a small fraction of γ-secretase is transported to the late compartments of the secretory pathway where substrates are encountered and subsequently processed.
My laboratory is committed to the studies designed to elucidate the regulatory mechanisms of assembly and intracellular trafficking of the γ-secretase complex and how the processes are misregulated by the disease-causing mutations and by other non-genetic risk factors. More specifically, current and future projects include
• Molecular mechanisms by which PEN-2 promotes PS1 cleavage.
• Identification of ER retention/retrieval factors for γ-secretase complex.
• Structure-function analysis of γ-secretase complex components.
• Molecular mechanisms by which FAD-associated PS1 mutants increase the Aβ42/Aβ40 ratio.
• Effects of potential risk factors for sporadic AD on the γ-secretase localization and activity.
We expect that t he results from these studies will not only contribute to our understanding of basic neurobiology of γ-secretase which is critical for degradation and signaling of selected membrane proteins, but also provide valuable new information relevant to the identification of novel targets for treatment and prevention of this devastating disease.
* Selected Publications
Kim SH , Wang R, Gordon DJ, Bass J, Steiner DF, Lynn DG, Thinakaran G, Meredith SC and Sisodia SS (1999) Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nature Neuroscience 2, 984-8.
Kim SH , Lah JJ, Thinakaran G, Levey A and Sisodia SS (2000) Subcellular localization of presenilins: Association with a unique membrane pool in cultured cells. Neurobiol. Dis . 7, 99-117 .
Kim SH , Leem JY, Lah JJ, Slunt HH, Levey H, Thinakaran G and Sisodia SS (2001) Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein. J. Biol. Chem. 276(46), 43343-50.
Cai D, Leem JY, Greenfield JP, Wang P, Kim BS, Wang R, Lopes KO, Kim SH , Zheng H, Greengard P, Sisodia SS, Thinakaran G, and Xu H (2002) Presenilin-1 regulates intracellular trafficking and cell surface delivery of β -amyloid precursor protein. J. Biol. Chem . 278(5), 3446-54.
Ikeuchi T, Dolios G, Kim SH, Wang R and Sisodia SS (2003) Familial Alzheimer disease-linked presenilin 1 variants enhance production of both Aβ1-40 and A β 1-42 peptides that are only partially sensitive to a potent aspartyl protease transition state inhibitor of " γ -secretase". J. Biol. Chem . 278(9), 7010-8.
Kim SH , Ikeuchi T, Yu C and Sisodia SS (2003) Regulated hyperaccumulation of presenilin-1 and the " γ-secretase" complex: Evidence for differential intramembranous processing of transmembrane substrates. J. Biol. Chem . 278(36), 33992-4002.
Kim SH, Yin YI, Li YM and Sisodia SS (2004) Evidence that assembly of an “active” γ-secretase complex occurs in the early compartments of the secretory pathway. J. Biol. Chem . 279(47), 48615-9.
Kim SH and Sisodia SS (2005) A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1. J. Biol. Chem . 280(3), 1992-2001.
Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes N, Parent A, Sisodia SS, and Thinakaran G (2005) Spatial segregation of γ -secretase and substrates in distinct membrane domains. J. Biol. Chem. 280(27):25892-900.
Kim SH and Sisodia SS (2005) Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J. Biol. Chem. 280(51):41953-66.
Location: http://www.med.ufl.edu/pharm/faculty/kim.shtml