Michael L. Shelanski, MD, PhD

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Overview
Credentials & Experience
Research

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

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.
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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, L?3pez-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.