Academic Appointments

Administrative Appointments

  • Professor & Chair, Stanford University School of Medicine - Comparative Medicine (1994 - 1009)

Honors & Awards

  • Diplomate, American College of Veterinary Pathologists (1975)
  • Distinguished Member, American College of Veterinary Pathologists (2002)
  • President, American College of Veterinary Pathologists (1996)
  • Councilor, American College of Veterinary Pathologists (1989-1992)
  • Active Member, Institute of Medicine (1988)
  • Distinguished Alumni, Texas A&M University (1991)
  • Fellow, American Association for the Advancement of Science (2005)

Professional Education

  • D.V.M., Texas A & M University, Veterinary Medicine (1970)
  • Ph.D., Washington State University, Experimental Pathology (1974)

Research & Scholarship

Current Research and Scholarly Interests

Animal models offer a unique opportunity to study the pathogenesis of neurologic diseases afflicting both humans and animals. For example, non-human primates develop many of the same cognitive deficits and neuropathologic changes as occur in humans. Inherited diseases in dogs reliably replicate many hereditary diseases in humans. We can learn much by studying the temporal and spatial evolution of the lesions in the nervous system in spontaneously occurring or induced diseases in animals.The rapid development of the dog genome map brings an important benefit to the study of inherited canine diseases. Comparative gene mapping among human, murine, and canine genomes have the potential to rapidly identify mutations that underlie various disease syndromes. My research focuses on the identification and characterization of animal models of human diseases. These animal models may occur in non-human primates, dogs, cats, goats, mice in which mutations have been induced, or in other less common laboratory species such as bears. By using these diverse species we can ask how the nervous system lesions are related to functional deficits? What is the biological significance of the lesions? How do the lesions begin? How do they evolve? What is the function of the cells early in disease when therapeutic intervention would be most advantageous? By evaluating the pathology and physiologic function or behavior in animals, we can begin to design rational interventional strategies to prevent, treat, or to delay the onset of neurodegenerative diseases.


Graduate and Fellowship Programs


All Publications

  • Allelic variants of the canine heavy neurofilament (NFH) subunit and extensive phosphorylation in dogs with motor neuron disease JOURNAL OF COMPARATIVE PATHOLOGY GREEN, S. L., Westendorf, J. M., Jaffe, H., Pant, H. C., CORK, L. C., Ostrander, E. A., Vignaux, F., Ferrell, J. E. 2005; 132 (1): 33-50


    Aberrant accumulation of extensively phosphorylated heavy (high molecular weight) neurofilament (NFH) and neurodegeneration are features of hereditary canine spinal muscular atrophy (HCSMA), an animal model of human motor neuron disease. In this study, the canine NFH gene was mapped, cloned, and sequenced, and electrospray/mass spectrometry was used to evaluate the phosphorylation state of NFH protein from normal dogs and dogs with HCSMA. The canine NFH gene was localized to a region on canine chromosome 26 that corresponds to human NFH on chromosome 22q. The predicted length of the canine NFH protein is 1135 amino acids, and it shares an 80.3% identity with human NFH and >74.6% with murine NFH proteins. Direct sequencing of NFH cDNA from HCSMA dogs revealed no mutations, although cDNA sequence and restriction fragment length polymorphism (RFLP) analysis indicates that there are at least three canine NFH alleles, differing in the position and number (61 or 62) of Lys-Ser-Proline (KSP) motifs. The two longest alleles (L1 and L2), each with 62 KSP repeats, contain an additional 24-base insert and were observed in both normal and HCSMA dogs. However, the shorter allele (the C allele), with 61 KSP sites and lacking the 24-base insertion, was absent in dogs with HCSMA. Mass spectrometry data indicated that almost all of the NFH KSP phosphorylation sites were occupied. No new or extra sites were identified in native NFH purified from the HCSMA dogs. The predominance of the two longest NFH alleles and the additional KSP phosphorylation sites they confer probably account for the presence of extensively phosphorylated NFs detected immunohistochemically in dogs with HCSMA.

    View details for DOI 10.1016/j.jcpa.2004.06.003

    View details for Web of Science ID 000226534700003

    View details for PubMedID 15629478

  • Structure, chromosomal location, and analysis of the canine Cu/Zn superoxide dismutase (SOD1) gene JOURNAL OF HEREDITY Green, S. L., Tolwani, R. J., Varma, S., Quignon, P., Galibert, F., CORK, L. C. 2002; 93 (2): 119-124


    Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.

    View details for Web of Science ID 000176888300006

    View details for PubMedID 12140271

  • Canine motor neuron disease: Clinicopathologic features and selected indicators of oxidative stress GREEN, S. L., Bouley, D. M., Pinter, M. J., CORK, L. C., Vatassery, G. T. WILEY-BLACKWELL PUBLISHING, INC. 2001: 112-119


    Hereditary canine spinal muscular atrophy (HCSMA) is an inherited motor neuron disease affecting a kindred of Brittanies. We have examined the clinicopathologic abnormalities in 57 animals with HCSMA, including 43 affected adult dogs and 14 homozygote pups. We also measured selected biochemical indices of oxidative stress: serum vitamin E (alpha-tocopherol) and Se concentrations; serum concentrations of Cu, Zn, Mg, and Fe; and total superoxide dismutase and glutathione peroxidase activities in red blood cells. Dogs with HCSMA had the following abnormalities: regenerative anemia, hypoglobulinemia, hypochloremia, and abnormally high creatine kinase and liver alkaline phosphatase activities. Serum Cu concentration was significantly (P = .01) increased in adult dogs with HCSMA compared to control dogs. Serum vitamin E concentrations tended to be lower in adult dogs with HCSMA compared to controls, and were significantly (P = .01) lower in homozygote pups compared to control pups.

    View details for Web of Science ID 000167403500006

    View details for PubMedID 11300593

  • The Neurobiology of Aging in Nonhuman Primates In: Alzheimer?s Disease, 2nd edition Cork LC, Walker LC 1999: 233-243
  • Hereditary canine spinal muscular atrophy is phenotypically similar but molecularly distinct from human spinal muscular atrophy JOURNAL OF HEREDITY Blazej, R. G., Mellersh, C. S., CORK, L. C., Ostrander, E. A. 1998; 89 (6): 531-537


    Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant motor neuron disease that is similar in pathology and clinical presentation to various forms of human motor neuron disease. We have tested the hypothesis that the canine survival motor neuron (SMN) gene is responsible for HCSMA by genetic and molecular analysis of a colony of mixed breed dogs, all descended from a single affected individual. We cloned the canine SMN gene and determined the DNA sequence in an affected and an unaffected dog. We found no germline mutations in the SMN gene of the affected individual. Using conventional linkage analysis with canine-specific microsatellite repeat markers we screened the canine genome and identified a single linkage group likely to contain the HCSMA gene. Analysis with a panel of canine/rodent hybrid cell lines revealed that the SMN gene did not map to the same chromosome as the HCSMA linkage group. Collectively these results suggest that the molecular basis for HCSMA is distinct from that of phenotypically similar human disorders caused by inherited mutations in the SMN gene. This further suggests that additional studies on the molecular nature of HCSMA may reveal an unknown element of the molecular pathway leading to motor neuron disease.

    View details for Web of Science ID 000078649100009

    View details for PubMedID 9864863

  • Alterations in cyclin-dependent protein kinase 5 (CDK5) protein levels, activity and immunocytochemistry in canine motor neuron disease JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY GREEN, S. L., Vulliet, P. R., Pinter, M. J., CORK, L. C. 1998; 57 (11): 1070-1077


    Hereditary canine spinal muscular atrophy (HCSMA) is a dominantly inherited motor neuron disease in Brittany spaniels that is clinically characterized by progressive muscle weakness leading to paralysis. Histopathologically, degeneration is confined to motor neurons with accumulation of phosphorylated neurofilaments in axonal internodes. Cyclin-dependent kinase 5 (CDK5), a kinase related to the cell cycle kinase cdc2, phosphorylates neurofilaments and regulates neurofilament dynamics. We examined CDK5 activity, protein levels, and cellular immunoreactivity in nervous tissue from dogs with HCSMA, from closely age-matched controls and from dogs with other neurological diseases. On immunoblot analysis, CDK5 protein levels were increased in the HCSMA dogs (by approximately 1.5-fold in both the cytosolic and the particulate fractions). CDK5 activity was significantly increased (by approximately 3-fold) in the particulate fractions in the HCSMA dogs compared to all controls. The finding that CDK5 activity was increased in the young HCSMA homozygotes with the accelerated form of the disease, who do not show axonal swellings histologically, suggests that alterations in CDK5 occurs early in the pathogenesis, prior to the development of significant neurofilament pathology. Immunocytochemically, there was strong CDK5 staining of the nuclei, cytoplasm and axonal processes of the motor neurons in both control dogs and dogs with HCSMA. Further immunocytochemical studies demonstrated CDK5 staining where neurofilaments accumulated, in axonal swellings in the dogs with HCSMA. Our observations suggest phosphorylation-dependent events mediated by CDK5 occur in canine motor neuron disease.

    View details for Web of Science ID 000077069800010

    View details for PubMedID 9825944

  • Hereditary canine spinal muscular atrophy: genetics, neurophysiology, and pathology CORK, L. C., GREEN, S. L., Pinter, M. J. ELSEVIER SCIENCE BV. 1997: S74-S74

    View details for Web of Science ID A1997YJ60100012

    View details for PubMedID 9419058

  • The costs of animal research: Origins and options SCIENCE CORK, L. C., Clarkson, T. B., Jacoby, R. O., Gaertner, D. J., LEARY, S. L., LINN, J. M., Pakes, S. P., Ringler, D. H., Strandberg, J. D., Swindle, M. M. 1997; 276 (5313): 758-759

    View details for Web of Science ID A1997WW90000046

    View details for PubMedID 9157554

  • Canine genetic linkage study using heterologous DNA probes JOURNAL OF HEREDITY Sack, G. H., Taylor, E. W., Meyers, D. A., Dragwa, C. R., CORK, L. C. 1996; 87 (1): 15-20


    We have used clones of 17 single-copy human DNA sequences to analyze their counterparts in the genome of the domestic dog by heterologous hybridization. Ten of the 17 sequences represented anchor loci proposed for comparative mammalian mapping. Eight of 17 human clones (including three of the anchor loci) gave clear hybridization signals when used with Southern blots of canine DNA. Five of these eight (including two anchor loci) showed diallelic restriction fragment length polymorphisms in a large kindred of Brittany spaniels and could be used for segregation studies. Several probes chosen from different human chromosomes also were unlinked in the dog. By contrast, linkage was found between the canine counterparts of the closely linked human serum amyloid A gene family. Three markers linked on human chromosome II appeared not to be syntenic in the dog. DNA markers linked to various human genetic neuromuscular diseases were not linked to hereditary canine spinal muscular atrophy which segregates in this kindred. However, there was evidence of possible linkage of this disorder with a canine counterpart of the tyrosinase gene. Segregation studies using heterologous single-copy DNA probes can be performed in dogs, but the level of inbreeding may reduce heterogeneity and limit the power of the analysis.

    View details for Web of Science ID A1996TY73600004

    View details for PubMedID 8742818