TitleMouse models for the neurodegenerative lysosomal storage diseases Niemann-Pick types C1 & C2 and classical late infantile neuronal ceroid lipofuscinosis
NameEl-Banna, Mukarram S. (author), Lobel, Peter (chair), Stock, Ann (internal member), Millonig, Jim (internal member), Rutgers University, Graduate School - New Brunswick,
SubjectMicrobiology and Molecular Genetics,
Lysosomal storage diseases
DescriptionUse of mutant mice provides us with an excellent tool for investigation of lysosomal diseases such as classical late infantile neuronal ceroid lipofuscinosis (cLINCL) and Niemann-Pick types C1 and C2 (NPC1 and NPC2). These are recessive devastating disorders in children that predominantly affect the central nervous system and result in progressive neurodegeneration and early death. Suitable mouse models enable us to assess behavioral, pathological, cellular, and molecular abnormalities associated with disease and to determine the efficacy of different therapeutic approaches. In addition, these models can be used to study the underlying function of the normal genes.
This thesis addresses the generation and characterization of mouse models for these diseases. These include creation of gene-targeted models for cLINCL and NPC2 diseases. Disease progression was monitored by assessing gross phenotype (weight), behavioral parameters such as trembling, gait analysis and survival. This and other analyses indicate that the gene targeted mice are good models for the human disease. We also created a mouse model with mutations in both Npc1 and Npc2. Comparison of the single and double deficient NPC mutants indicate that the NPC1 and NPC2 proteins function in a common pathway. We also created mutant mice that expressed different levels of tripeptidyl peptidase 1 (TPP1), the protein deficient in cLINCL. This allowed estimation of how much protein is necessary to achieve therapeutic benefits.
Immunohistochemistry serves an important role in studying these mouse models and determining the distribution of the normal proteins. This is especially important when looking at protein distributions within the brain following gene or enzyme replacement therapy. We describe development of procedures to visualize TPP1, NPC1, and NPC2 in mouse brain.
NoteIncludes bibliographical references (p. 63-71)
Noteby Mukarram S. El-Banna
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
RightsThe author owns the copyright to this work.