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

  • The non-human primate striatum undergoes marked prolonged remodeling during postnatal development FRONTIERS IN CELLULAR NEUROSCIENCE Martin, L. J., Cork, L. C. 2014; 8
  • The non-human primate striatum undergoes marked prolonged remodeling during postnatal development. Frontiers in cellular neuroscience Martin, L. J., Cork, L. C. 2014; 8: 294-?


    We examined the postnatal ontogeny of the striatum in rhesus monkeys (Macaca mulatta) to identify temporal and spatial patterns of histological and chemical maturation. Our goal was to determine whether this forebrain structure is developmentally static or dynamic in postnatal life. Brains from monkeys at 1 day, 1, 4, 6, 9, and 12 months of age (N = 12) and adult monkeys (N = 4) were analyzed. Nissl staining was used to assess striatal volume, cytoarchitecture, and apoptosis. Immunohistochemistry was used to localize and measure substance P (SP), leucine-enkephalin (LENK), tyrosine hydroxylase (TH), and calbindin D28 (CAL) immunoreactivities. Mature brain to body weight ratio was achieved at 4 months of age, and striatal volume increased from ?1.2 to ?1.4 cm(3) during the first postnatal year. Nissl staining identified, prominently in the caudate nucleus, developmentally persistent discrete cell islands with neuronal densities greater than the surrounding striatal parenchyma (matrix). Losses in neuronal density were observed in island and matrix regions during maturation, and differential developmental programmed cell death was observed in islands and matrix regions. Immunohistochemistry revealed striking changes occurring postnatally in striatal chemical neuroanatomy. At birth, the immature dopaminergic nigrostriatal innervation was characterized by islands enriched in TH-immunoreactive puncta (putative terminals) in the neuropil; TH-enriched islands aligned completely with areas enriched in SP immunoreactivity but low in LENK immunoreactivity. These areas enriched in SP immunoreactivity but low in LENK immunoreactivity were identified as striosome and matrix areas, respectively, because CAL immunoreactivity clearly delineated these territories. SP, LENK, and CAL immunoreactivities appeared as positive neuronal cell bodies, processes, and puncta. The matrix compartment at birth contained relatively low TH-immunoreactive processes and few SP-positive neurons but was densely populated with LENK-immunoreactive neurons. The nucleus accumbens part of the ventral striatum also showed prominent differences in SP, LENK, and CAL immunoreactivities in shell and core territories. During 12 months of postnatal maturation salient changes occurred in neurotransmitter marker localization: TH-positive afferents densely innervated the matrix to exceed levels of immunoreactivity in the striosomes; SP immunoreactivity levels increased in the matrix; and LENK-immunoreactivity levels decreased in the matrix and increased in the striosomes. At 12 months of age, striatal chemoarchitecture was similar qualitatively to adult patterns, but quantitatively different in LENK and SP in caudate, putamen, and nucleus accumbens. This study shows for the first time that the rhesus monkey striatum requires more than 12 months after birth to develop an adult-like pattern of chemical neuroanatomy and that principal neurons within striosomes and matrix have different developmental programs for neuropeptide expression. We conclude that postnatal maturation of the striatal mosaic in primates is not static but, rather, is a protracted and dynamic process that requires many synchronous and compartment-selective changes in afferent innervation and in the expression of genes that regulate neuronal phenotypes.

    View details for DOI 10.3389/fncel.2014.00294

    View details for PubMedID 25294985

  • 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

  • Reduced endplate currents underlie motor unit dysfunction in canine motor neuron disease JOURNAL OF NEUROPHYSIOLOGY Rich, M. M., Waldeck, R. F., CORK, L. C., Balice-Gordon, R. J., Fyffe, R. E., Wang, X. Y., Cope, T. C., Pinter, M. J. 2002; 88 (6): 3293-3304


    Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant degenerative disorder of motor neurons. In homozygous animals, motor units produce decreased force output and fail during repetitive activity. Previous studies suggest that decreased efficacy of neuromuscular transmission underlies these abnormalities. To examine this, we recorded muscle fiber endplate currents (EPCs) and found reduced amplitudes and increased failures during nerve stimulation in homozygotes compared with wild-type controls. Comparison of EPC amplitudes with muscle fiber current thresholds indicate that many EPCs from homozygotes fall below threshold for activating muscle fibers but can be raised above threshold following potentiation. To determine whether axonal abnormalities might play a role in causing motor unit dysfunction, we examined the postnatal maturation of axonal conduction velocity in relation to the appearance of tetanic failure. We also examined intracellularly labeled motor neurons for evidence of axonal neurofilament accumulations, which are found in many instances of motor neuron disease including HCSMA. Despite the appearance of tetanic failure between 90 and 120 days, average motor axon conduction velocity increased with age in homozygotes and achieved adult levels. Normal correlations between motor neuron properties (including conduction velocity) and motor unit properties were also observed. Labeled proximal motor axons of several motor neurons that supplied failing motor units exhibited little or no evidence of axonal swellings. We conclude that decreased release of transmitter from motor terminals underlies motor unit dysfunction in HCSMA and that the mechanisms determining the maturation of axonal conduction velocity and the pattern of correlation between motor neuron and motor unit properties do not contribute to the appearance or evolution of motor unit dysfunction.

    View details for DOI 10.1152/jn.00270.2002

    View details for Web of Science ID 000179865600033

    View details for PubMedID 12466447

  • 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

  • Per diem rates and true costs: Apples and oranges COMPARATIVE MEDICINE CORK, L. C. 2002; 52 (1): 10-11

    View details for Web of Science ID 000174194200001

    View details for PubMedID 11900408

  • 2000 Report of the AVMA Panel on Euthanasia JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION Beaver, B. V., Reed, W., Leary, S., McKiernan, B., Bain, F., Schultz, R., Bennett, B. T., Pascoe, P., Shull, E., CORK, L. C., Francis-Floyd, R., Amass, K. D., Johnson, R., Schmidt, R. H., Underwood, W., Thornton, G. W., Kohn, B. 2001; 218 (5): 669-696

    View details for Web of Science ID 000167192700018

    View details for PubMedID 11280396

  • Canine motor neuron disease: Clinicopathologic features and selected indicators of oxidative stress 17th Annual Meeting of the American-College-of-Veterinary-Internal-Medicine GREEN, S. L., Bouley, D. M., Pinter, M. J., CORK, L. C., Vatassery, G. T. WILEY-BLACKWELL PUBLISHING, INC. 2001: 112?19


    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
  • 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 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

  • Life-long overexpression of S100 beta in Down's syndrome: Implications for Alzheimer pathogenesis NEUROBIOLOGY OF AGING Griffin, W. S., Sheng, J. G., MCKENZIE, J. E., Royston, M. C., Gentleman, S. M., Brumback, R. A., CORK, L. C., Del Bigio, M. R., Roberts, G. W., Mrak, R. E. 1998; 19 (5): 401-405


    Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. Such plaques are virtually universal in middle-aged Down's syndrome, making Down's a natural model of Alzheimer's disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down's syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Down's patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down's patients. The numbers of S100beta+ astrocytes in young and adult Down's patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Down's syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimer's disease.

    View details for Web of Science ID 000077725500005

    View details for PubMedID 9880042

  • Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency JOURNAL OF IMMUNOLOGY Ameratunga, R., Winkelstein, J. A., Brody, L., Binns, M., CORK, L. C., Colombani, P., Valle, D. 1998; 160 (6): 2824-2830


    Genetically determined deficiency of the third component of complement (C3) in the dog is characterized by a predisposition to recurrent bacterial infections and to type 1 membranoproliferative glomerulonephritis. The current studies were undertaken to characterize the cDNA for wild-type canine C3 and identify the molecular basis for hereditary canine C3 deficiency. Amplification, cloning, and sequence analysis indicated that canine C3 is highly conserved in comparison with human, mouse, and guinea pig C3. Southern blot analysis failed to show any gross deletions or rearrangements of DNA from C3-deficient animals. Northern blot analysis indicated that the livers of these animals contain markedly reduced quantities of a normal length C3 mRNA. The full-length 5.1-kb canine C3 cDNA was amplified in overlapping PCR fragments. Sequence analysis of these fragments has shown a deletion of a cytosine at position 2136 (codon 712), leading to a frameshift that generates a stop codon 11 amino acids downstream. The deletion has been confirmed in genomic DNA, and its inheritance has been demonstrated by allele-specific oligonucleotide hybridization.

    View details for Web of Science ID 000072402900036

    View details for PubMedID 9510185

  • Effects of 4-aminopyridine on muscle and motor unit force in canine motor neuron disease JOURNAL OF NEUROSCIENCE Pinter, M. J., Waldeck, R. F., Cope, T. C., CORK, L. C. 1997; 17 (11): 4500-4507


    Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage-dependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.

    View details for Web of Science ID A1997XA05600053

    View details for PubMedID 9151766

  • 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



    In the course of maintaining a large colony of Brittany spaniels for studying a dominantly inherited motor neuron trait, cases of sporadic complete cleft palate were observed. Without intervention, the pups with cleft palate that attempt to nurse, aspirate and die. In this study, we report on the incidence of cleft palate in this dog kindred, describe the gross morphologic characteristics of the cleft, and present a morphometric analysis of the skull of two of the cleft palate pups and one unaffected pup that died at birth. Our data thus far indicate 26.9% incidence of cleft palate in the colony. Pedigree analysis indicates that this cleft palate trait is inherited as an autosomal recessive. High resolution computed tomography scans of the pup heads were used in morphometric comparison of normal and cleft palate pups. We found specific morphologic differences between the cranial base and palate of normal and cleft palate pups. Plans for future studies of the genetics and growth and development of this animal model are discussed. This canine cleft palate trait provides an ideal model for studying a malformation common in humans.

    View details for Web of Science ID A1994PN85500005

    View details for PubMedID 7986797

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