Laboratory of Neuronal Cell Death Mechanisms

Neville Marks, Ph.D., Principal Research Scientist
Martin J. Berg, M.S. and Margaret A. Reilly, Ph.D., Research Associates
Mitsuo Saito, Ph.D. and Mariko Saito, Ph.D., Associates

Unscheduled neuronal cell loss is a hallmark feature of cognitive dysfunction in dementia. The lab is examining roles for death effector caspases as moderators in isolated primary neurons or neuroblastoma N2a as models following treatment with apoptotic or necrotic stressors. The lab also focuses on roles of other cysteine proteases of lysosomal origin including cathepsins B and L as well as peptidases known as secretases implicated in the turnover of the Alzheimer's amyloid precursor protein that yield the amyloid peptide characteristic of extracellular lesions. These enzymes appear to also take part in numerous signaling pathways and have general function in maintaining cellular homeostasis. Here we investigate their characterization and specificity using various cell biological techniques such as enzymology, microscopy and imaging and innovative approaches involving gene silencing.

We are also evaluating pathways of cell death moderated by lipids acting as second messengers from the ceramide-sphingomyelin cycle. These include the afore-mentioned and their metabolites, the simple and complex sphingolipids such as glc- and lac-ceramide and gangliosides GM1, GD1a, GT1b, and GD3. These appear to not only maintain membrane stability and fluidity, but also to have positive or negative effects on neuronal survival and differentiation, which therefore have implications for non-amyloidogenic neurodegeneration, and afford avenues for new areas of therapeutic intervention.

Amelioration of bipolar disorders by lithium (Li+) and other agents may reflect novel neurotrophic properties as shown in this lab, and provides scope to investigate roles pharmacological agents may play in neuronal viability and neuroprotection depending on a neuron's developmental states.

Neville Marks received his Ph.D. from the University of London Institute of Psychiatry. He formerly held positions at Northwestern University, the University of Michigan, and Columbia University. He joined the New York State Institute of Neurochemistry and Drug Addiction that merged with the Rockland Research Institute to become the Nathan S. Kline Institute for Psychiatric Research. He is also an Associate Professor of Psychiatry at the New York University School of Medicine. Neville has been awarded numerous grants from federal agencies (NIH, NIDA) and from private sources such as the M.S. and Kroc Foundations.

Martin Berg received his B.S. from the University of South Florida in 1979, and his M.S. from Fordham University in 1990. He has been employed as a Research Scientist at NKI since 1980.

Margaret Reilly earned her Ph.D. in Pharmacology from New York Medical College. She has been a Research Scientist at NKI since 1966. Margaret has also had numerous teaching appointments including Adjunct Associate Professor of Pharmacology at the College of New Rochelle School of Nursing from 1978 to 1992. She is presently an Instructor in Pharmacology at Phillips Beth Israel School of Nursing and Adjunct Assistant Professor of Pharmacology at Concordia College/Mount Vernon Hospital School of Nursing.

Recent Publications from the Lab:

Research Reports

K. Ditaranto-Desimone, M. Saito, T.L. Tekirian, M. Saito, M. Berg, G. Dubowchik, B. Soreghan, S. Thomas, N. Marks, and A.J. Yang. (2003) Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide. Brain Res. Bull.:523-531.

N. Marks, M. Saito, M. Green, M.A. Reilly, A.J. Yang, K. Ditaranto, and M.J. Berg. (2001) Opposite effects of lithium on proximal and distal caspases of immature and mature primary neurons correlate with earlier paradoxical actions on viability. Neurochem. Res.:1311-1320.

A.A. Galoyan, N. Terio, M.J. Berg, and N. Marks. (2000) Effects of proline-rich peptide (PRP) derived from neurophysin-II on caspases of murine neuroblastoma: evidence for caspase-2 and -6 activation. Neurokhimija:185-188.

M. Saito, M.J. Berg, A. Guidotti, and N. Marks.(1999) Gangliosides attenuate ethanol-induced apoptosis in cerebellar granule neurons. J. Neurochem. Res.:1109-1117.

M. Saito, A. Guidotti, M.J. Berg, and N. Marks.(1998) The semisynthetic glycosphingolipid LIGA₂₀ potently protects neurons against apoptosis. Ann. NY Acad. Sci.:253-262.

N. Marks, M.J. Berg, M. Saito, and A. Guidotti. (1998) Activation of caspase-3 and apoptosis in cerebellar granule cells. J. Neurosci. Res.:334-341.

M.J. Berg, R. Durrie, V.S. Sapirstein, and N. Marks. (1997) Composition of white matter bovine brain coated vesicles: evidence that several components influence beta-amyloid peptide to form oligomers and aggregates in vitro. Br. Res. 752:72-80.

A. Oberto, N. Marks, H.L. Evans, and A. Guidotti, A. (1996) Lead (Pb+2) promotes apoptosis in newborn rat cerebellar neurons: pathological implications. J. Pharmacol. Exp. Therapeut.:435-442.

Reviews

N. Marks and M.J. Berg. (2003) APP processing enzymes (secretases) as therapeutic targets: insights from the use of transgenics (Tgs) and transfected cells. Neurochem. Res.:1049-1062. N. Marks and M.J. Berg. (2001) Amyloid (TACE, BACE) and presenilin proteases associated with Alzheimer's disease. In: The role of proteases in the pathophysiology of neurodegenerative diseases. Eds. N.E. Banik and A. Lajtha. Kluwer Academic/Plenum Publishers, New York, N.Y. pp. 155-178.

N. Marks and M.J. Berg.(1999) Recent advances in neuronal caspases in development and neurodegeneration. Neurochem. Int.:195-220.

N. Marks and M.J. Berg. (1997) Genetic and risk factors in Alzheimer's Disease (AD). Neurokhimija:131-153.

Selected Abstracts

N. Marks and M.J. Berg (2004) Sphingomyelin (SM) hydrolysis and synthesis as factors influencing viability of isolated cerebellar granule cells and their potential relevance to pathology. Proc. Soc. Neurosci. 35 (in press).

N. Marks, M.J. Berg, M. Saito, and M. Saito (2002) Glucosylceramide synthase inhibitor d-threo P4 mediated cytotoxicity on mature cerebellar granule neurons is caspase-independent: Cer/glycolipids as a determinant. Proc. Soc. Neurosci. 33:100.6