Michael L. Shelanski, MD, PhD

  • Henry Taub Professor of Alzheimer's Disease and the Aging Brain (in Pathology and Cell Biology and in the Taub Institute)
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Overview

Dr. Shelanski's laboratory is investigating the mechanism of memory disruption and synaptic dysfunction in Alzheimer's Disease. They use a combination of cell culture and transgenic animal approaches in an attempt to understand why the overexpression of the amyloid precursor protein (APP) or direct application of its active peptide, A-beta, inhibits intracellular signaling in neuronal cells and leads to alterations of electrical activity, dendritic spine morphology and behavior. These results are extended with analyses of neurons taken from post-mortem Alzheimer's Disease brains.

In the past two years their attention has been on the PKA-CREB signaling pathway and on the role of ubiquitin c-terminal hydrolase-L1 (Uch-L1) in regulating these events. They have used both drugs and protein transduction techniques to show that A-beta induced changes, both in culture and in the animal, can be reversed by restoring these pathways to their normal "balance". Other projects involve the induction of neurogenesis in neural stem cells by A-beta raising the possibility of an endogenous repair mechanism in AD, and the analysis of the action of the ginkgolides on neuronal function.

The laboratory approaches these questions with a wide range of tools including biochemistry, cell biology, physiology and microscopy.

Email: mls7@cumc.columbia.edu

Academic Appointments

  • Henry Taub Professor of Alzheimer's Disease and the Aging Brain (in Pathology and Cell Biology and in the Taub Institute)

Administrative Titles

  • Senior Vice Dean for Research
  • Co-Director, Taub Institute for Research on Alzheimer's Disease and the Aging Brain

Languages

  • French
  • German

Gender

  • Male

Credentials & Experience

Education & Training

  • MD, PhD, 1966 Cell Biology, University of Chicago Pitzker School of Medicine
  • Residency: 1979 Bronx Municipal Hosp., Albert Einstein
  • Fellowship: 1967 University of Chicago

Committees, Societies, Councils

Scientific Review Committees:

Neurology A Study Section, National Institutes of Health, 1974-1978.

Chairman, Overhead Power Lines Advisory Committee, NYS Dept. Health, 1981-87

Committee on Non-ionizing Radiation, Comm. on Life Science, NRC/NAS, 1986

Alzheimer's Disease and Related Disorders Assn. Scientific Advisory Board, 1985 - 92

National Board of Directors, 1990-92; Zenith Award Committee, 1993-95

Pharmacological Sciences Study Section, NIGMS, 1986-1990

American Cancer Society Institutional Review Panel, 1988-93

Member, Scientific Advisory Board, Dystonia Society, 1990-1995

Member, Scientific Advisory Board, ALS Association, 1990-1994

Board of Trustees (Ex-officio), Presbyterian Hospital in the City of New York, 1990-1998

Special Study Sections for Udall Parkinson’s Disease Centers 1998, 1999, 2003, 2004, 2008, 2010 Chairman 2005,2006,

Special Review Panel, Evaluation of BDCN Study Sections, CSR/NIH. 2000

K99 Review Panel NINDS, 2007, NSD-B 2008

Co-Chairman, Biology and Biomedicine Evaluation Committee, Consejo Superior de Investigationes Cientificas (Spanish National Science Foundation, 22 Institutes), Madrid 2009.

RC1 and RC2 Review Panels NIH 2009

Member, College of CSR Reviewers, 2010 –

Member, IOM AFIP Committee 2012 (Future Uses of DoD Joint Pathology Center Biorepository – published 2013)

Member of IOM Committee on Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2014).

Advisory Boards:

Scientific Advisory Board, International Conf. on Alzheimer’s Disease, 1992-1999

President Medical Board, Presbyterian Hospital in the City of New York, 1994-1997

Technology Advisory Council, Fisher Scientific International, Inc. 1996-2007

External Advisory Boards of the Alzheimer’s Disease Research Centers at Harvard (1990-95).

Johns Hopkins (1990-1995), San Diego (1989–2014, Chairman), UC Irvine-USC (1996 -98)

Scientific Advisory Committee, Institut du Cerveau et de la Moelle épinière,, Paris, Fr. 2005-

Board of Directors, Burke Research Institute , White Plains, NY 2004-

Board of Directors, N. Bud Grossman Center for Memory Research and Care, U.of Minnesota 2007 -

President, Scientific Advisory Board, Institut du Cerveau et de la Moelle épinière,, Paris, Fr. 2009 –

Editorial Boards:

Editorial Board, Journal of Mechanochemistry and Cell Motility, 1973-1975.

Editorial Board, Journal of Neurochemistry, 1982-1990

Editorial Board, New York University Press, 1984-87

Editorial Board, J. Neuropathology and Experimental Neurology, 1983- 1985

Editorial Board, Neurobiology of Aging, 1987 -

Editorial Board, Neuroscience, 1985-1990

Editorial Board, Laboratory Investigation, 1989 -1996

Editorial Board, Brain Pathology 1990-1993

Associate Editor, The Journal of Neuroscience, 1999-2004

Honors & Awards

  • Alpha Omega Alpha
  • Teacher-Investigator Award, NINCDS, 1971-74
  • Guggenheim Foundation Fellow, 1973-1974
  • McKnight Scholar in Neurosciences 1977-84
  • Javits Neuroscience Investigator Award NINCDS 1994-2001
  • Association of American Physicians
  • National Academy of Medicine 1999

Research

We are using a combination of cell biological and molecular biological approaches, including anti-sense technology, to study the function of two proteins: the intermediate filament peripherin and the high molecular weight form of the microtubule associated protein tau. These proteins are characteristic of the cytoskeleton of the peripheral neuron. We are interested in why there are differences between the central and peripheral cytoskeleton and whether these differences are related to the greater regenerative potential of peripheral neurons. To aid in this effort we have set up a model "axon" using baculovirus expression and insect SF9 cells to assess interactions between specific cytoskeletal components. A related series of studies is investigating the mechanism by which astrocytes and neurons initiate the formation of long asymmetric processes. Our approach has shown that process formation in the astrocyte is inhibited by the cortical actin network and favored by the assembly of microtubules. This equilibrium is controlled by the myosin light chain kinase acting on the myosin light chain and on destrin, an actin-severing protein. These studies utilize a variety of cell biology approaches including biochemistry, EM, optical imaging and antisense oligonucleotides. Other research in the laboratory is on the role of cytokines, specifically IL-1, on the development of cytoskeletal changes in Alzheimer's disease.

 

Research Interests

  • Cytoskeleton and Neural Development
  • Neural Degeneration and Repair

Selected Publications

Aubry S, Shin W, Crary JF, Lefort R, Qureshi YH, Lefebvre C, Califano A, Shelanski ML. (2015) Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression. PloS one. 10(3):e0120352. doi: 10.1371/journal.pone.0120352.

Padmanabhan J, Brown KR, Padilla A, Shelanski ML. (2015) Functional role of RNA polymerase II and P70 S6 kinase in KCl withdrawal-induced cerebellar granule neuron apoptosis. The Journal of biological chemistry. 290:5267-79. doi: 10.1074/jbc.M114.575225.

Pasini S, Corona C, Liu J, Greene LA, Shelanski ML. (2015) Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory. Cell Reports. 11:183-91.

Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, Tuschl T, Clark LN, Shelanski ML, McCabe BD, Crary JF. (2015) Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. The Journal of clinical investigation. 125:681-6. doi: 10.1172/JCI78421.

Shelanski M, Shin W, Aubry S, Sims P, Alvarez MJ, Califano A. (2015) A systems approach to drug discovery in Alzheimer's disease. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics. 12:126-31. doi: 10.1007/s13311-014-0335-5.

Liu J, Pasini S, Shelanski ML, Greene LA. (2014) Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology. Frontiers in cellular neuroscience. 8:177. doi: 10.3389/fncel.2014.00177.

Sproul AA, Vensand LB, Dusenberry CR, Jacob S, Vonsattel JP, Paull DJ, Shelanski ML, Crary JF, Noggle SA. (2014) Generation of iPSC lines from archived non-cryoprotected biobanked dura mater. Acta Neuropathol Commun. 2:4. doi: 10.1186/2051-5960-2-4.

Poon WW, Carlos AJ, Aguilar BL, Berchtold NC, Kawano CK, Zograbyan V, Yaopruke T, Shelanski M, Cotman CW. (2013) β-Amyloid (Aβ) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1. J Biol Chem. 288:16937-48.

Pozueta J, Lefort R, Ribe EM, Troy CM, Arancio O, Shelanski M. (2013) Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun. 4:1939.

Zou, F et al. (2012) Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants PLoS Genet. 8(6):e1002707 doi: 10.1371/journal.pgen.1002707.

Lefort R, Pozueta J, shelandki M (2012) Cross-linking of cell surface amyloid precursor protein leads to increased β-amyloid peptide production in hippocampal neurons: implications for Alzheimer's disease. J. Neurosci. 32:10674-85.

Malagelada C, López-Toledano MA, Willett RT, Jin ZH, Shelanski ML, Greene LA (2011) RTP801/REDD1 regulates the timing of cortical neurogenesis and neuron migration J Neurosci. 3:3186-96.

Naj AC, et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease Nat Genet. 43:436-41.