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William W. Schlaepfer, MD

William W. Schlaepfer, MD Physician

Emeritus Professor of Pathology and Laboratory Medicine

Dr. Schlaepfer is a Penn Medicine employed physician.

About Dr. William W. Schlaepfer

Recognized by America's Top Doctors, 2007

Recognized in Philadelphia Magazine's May 2004, 2005 Top Docs issue

Clinical Specialties

Specialty:

  • Pathology and Laboratory Medicine

Programs & Centers:

Board Certification:

  • Pathology - Anatomic Pathology, 1964
  • Pathology - Neuropathology, 1964

Description of Clinical Expertise

Peripheral Nerve Disease

Practice Locations and Appointments

Insurance Accepted

  • Aetna US Healthcare
  • Cigna
  • Cigna HealthSpring
  • Devon Health Services (Americare)
  • Gateway Health Plan
  • Geisinger Health Plan
  • HealthAmerica / HealthAssurance, a Coventry Plan
  • HealthPartners
  • HealthSmart
  • Highmark Blue Shield
  • Horizon Blue Cross Blue Shield of New Jersey
  • Humana / Choicecare
  • Independence Blue Cross (Keystone East)
  • Intergroup
  • Keystone First
  • Multiplan
  • NJ Medicaid
  • NJ Qualcare
  • Oxford Health Plan
  • PA Medicaid
  • PA Medicare
  • Rail Road Medicare / Palmetto GBA
  • Tricare
  • United Healthcare
  • UnitedHealthcare Community Plan
  • US Family Health Plan

Education and Training

Medical School: Yale University School of Medicine
Residency: Yale-New Haven Hospital
Fellowship: Max Planck Institute for Psychiatry
Fellowship: Yale-New Haven Hospital

Memberships

American Association of Neuropathologists,

Hospital Affiliation

Dr. Schlaepfer is a Penn Medicine employed physician.

Hospital Privileges:

  • Hospital of the University of Pennsylvania: On the medical staff, but does not have privileges to treat patients in the hospital.
  • Penn Presbyterian Medical Center: On the medical staff, but does not have privileges to treat patients in the hospital.
  • Pennsylvania Hospital: On the medical staff, but does not have privileges to treat patients in the hospital.

Research

Description of Research Expertise:

Our laboratory has a long-standing interest in the structural, biochemical and molecular properties of neurofilament (NF) proteins. These studies are now directed at mechanisms whereby disruption of NF assembly and aggregation of the light neurofilament (NFL) protein lead to motor neuron degeneration and disease. Although accumulations of NFs in neurons-at-risk have long been regarded as a reactive or secondary event in neuronal disease, there is new and growing evidence that alterations in assembly and aggregation of NFL play a primary role in the pathogenesis of motor neuron disease. The driving force behind the new direction of study has been the discovery that mutations in NFL and in small heat shock proteins, HSPB1 and HSPB8, cause motor neuron degeneration in CMT2E, CMT2F and CMT2L forms of Charcot-Marie-Tooth (CMT) disease.


Disease-causing mutations in NFL, HSPB1 and HSPB8 are known to disrupt assembly and lead to aggregation of NFL protein. We show that expression of CMT-mutant NFL or HSPB1 directly in motor neurons disrupts NF assembly, leads to aggregation of NFL protein and causes progressive degeneration and loss of viability of motor neurons. Most importantly, we show that the neurotoxic effects are dependent on the presence of the NFL gene or gene products in motor neurons. The findings support a working hypothesis that disruption of assembly and aggregation of NFL protein are part of a pathway leading to motor neuron degeneration. The hypothesis argues that the pathogenesis of motor neuron disease is characterized by the same features as found in other major neurodegenerative diseases; namely, that abnormal protein aggregation is a triggering event in the degeneration of neurons-at-risk and that aggregation of widely expressed proteins leads to highly selective degeneration of a very small subset of neurons-at-risk in disease states.


Ongoing studies also suggest that aggregation and neurotoxicity of NFL have synergistic affects on the aggregation and neurotoxicity of mutant SOD1 protein. These findings raise the possibility that aggregation and neurotoxicity of NFL could contribute to the specific degeneration of motor neurons from widely expressed proteins, such as mutant SOD1, that are destabilized by missense mutations and prone to undergo aggregation in disease-associated tissues. The findings lend further support to the underlying premise that NF assembly is important for maintaining homeostasis of motor neurons and that disrupted assembly and aggregation of NFL protein can trigger motor neuron degeneration and motor neuron disease. Disrupted assembly and aggregation of NFL may therefore provide a starting point for dissecting the upstream and downstream pathways that lead to specific motor neuron degeneration and for developing effective therapeutic remedies for motor neuron disease based on an understanding of underlying pathogenetic mechanisms

Selected Publications:

Lin H, Zhai J, Cañete-Soler R, Schlaepfer WW: 3'untranslated region in a light neurofilament (NF-L) mRNA triggers aggregation of NF-L and mutant superoxide dimutase 1 proteins in neuronal cells Journal of Neuroscience 24 (11): 2716-26,2004.

Wu J, Zhai J, Lin H, Nie Z, Ge WW, Garcia-Bermejo L, Muschel RJ, Schlaepfer WW, Cañete-Soler R: Cytoplasmic retention sites in p190RhoGEF confer anti-apoptotic activity to an EGFP-tagged protein Molecular Brain Research 117 (1): 27-38,2003.

Lin H, Zhai J, Nie Z, Wu J, Meinkoth JL, Schlaepfer WW, Cañete-Soler R: Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons Journal of Neuropathology & Experimental Neurology 62 (9): 936-50,2003.

Zhai J, Lin H, Nie Z, Wu J, Cañete-Soler R, Schlaepfer WW, Schlaepfer DD: Direct interaction of focal adhesion kinase with p190RhoGEF Journal of Biological Chemistry 278 (27): 24865-73,2003.

Ge W, Wu J, Zhai J, Nie Z, Lin H, Schlaepfer WW, Cañete-Soler R: Binding of p190RhoGEF to a destabilizing element on the light neurofilament mRNA is competed by BC1 RNA Journal of Biological Chemistry 277 (45): 42701-5,2002.

Nie Z, Wu J, Zhai J, Lin H, Ge W, Schlaepfer WW, Cañete-Soler R: Untranslated element in neurofilament mRNA has neuropathic effect on motor neurons of transgenic mice Journal of Neuroscience 22 (17): 7662-70,2002.

Zhai J, Lin H, Shamim M, Schlaepfer WW, Cañete-Soler R: Identification of a novel interaction of 14-3-3 with p190RhoGEF Journal of Biological Chemistry 276 (44): 41318-24,2001.

Cañete-Soler R, Wu J, Zhai J, Shamim M, Schlaepfer WW: p190RhoGEF Binds to a destabilizing element in the 3' untranslated region of light neurofilament subunit mRNA and alters the stability of the transcript Journal of Biological Chemistry 276 (34): 32046-50,2001.

Cañete-Soler R, Schlaepfer WW: Similar poly(C)-sensitive RNA-binding complexes regulate the stability of the heavy and light neurofilament mRNAs Brain Research 867 (1-2): 265-79,2000.

Cañete-Soler R, Silberg DG, Gershon MD, Schlaepfer WW: Mutation in neurofilament transgene implicates RNA processing in the pathogenesis of neurodegenerative disease Journal of Neuroscience 19 (4): 1273-83,1999.

Academic Contact Info

609C Stellar Chance Bldg.
422 Curie Blvd.

Philadelphia, PA 19104

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