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Robert
W. Doms, Ph.D.
Professor, Department of Pathology
and Laboratory Medicine
School of Medicine
806 Abramson Building
(215) 898-0890 FAX: (215) 573-2883
email: doms@mail.med.upenn.edu Lorem ipsum
Click here for selected publications since Dr. Doms's arrival at Penn
RESEARCH INTERESTS
Cell biology of membrane proteins involved in Alzheimer's disease pathogenesis;
Viral neuropathogenesisRESEARCH TECHNIQUES
Viral vectors, including lentivirus vectors; model in vitro neuronal systems; molecular biology; cell biological techniques to study protein transport and processing; studies with HIV-1 and SIVRESEARCH SUMMARY
Three membrane proteins have been identified that, if they harbor particular point mutations, inevitably lead to the development of Alzheimer's disease. These proteins are the amyloid precursor protein (APP), presenilin-1 (PS1) and presenilin-2 (PS2). An important pathological feature of Alzheimer's disease is the accumulation of senile plaques composed predominantly of amyloid-b (Ab) peptide. The Ab peptide is generated from proteolytic processing of APP, a type I transmembrane glycoprotein. APP is cleaved by two distinct enzymatic activities which result in the production of an array of Ab species that differ only slightly in length but vary greatly in their abilities to aggregate. In the amyloidgenic pathway, APP is first cleaved by BACE, which cuts at an extraluminal site generating a C-terminal APP fragment, and subsequently within its transmembrane domain by g-secretase to generate Ab peptides and an intracellular APP C-terminal domain.The g-secretase is a complex of four noncovalently associated protein components that appear to be sufficient for enzymatic activity. The active site of the complex has been shown to reside in presenilin-1 (PS1) or its closely related isoform PS2, which are predicted to traverse the membrane eight times. However, for PS1 to attain enzymatic function, it must associate with three other integral membrane proteins, nicastrin (NCT), APH-1 and PEN-2. PEN-2 is a 101 amino acid long protein which we found traverses the membrane twice, with both its C- and N-terminal domains facing the lumen of the endoplasmic reticulum (ER). APH-1 is predicted to traverse the membrane seven times. NCT is a type I transmembrane protein containing multiple glycosylation sites, and has been shown to be essential for APP processing and Notch signaling. Studies performed in Drosophila melongaster have shown that NCT appears to stabilize PS1 and to be critical for trafficking of PS to the cell surface. Conversely, PS1 is required for the maturation and trafficking of NCT. Much of our work in this area concerns the structure and function of the g-secretase complex. How do these 4 proteins interact with each other? What are their functions? How is the activity of this complex regulated?
KEY WORDS:
Alzheimer's disease, APP, presenilin, HIV-1, SIV, neuropathogenesis, NT2N neurons
Doms Lab
