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Evaluation of Potential Therapeutic Targets for Classic Late Infantile Neuronal Ceroid Lipofuscinosis

by
Kwi-Hye Kim
MS, 2002
Albany Medical College

Thesis Advisor: Peter Lobel, PhD
Graduate Program of Molecular Genetics, Microbiology and Immunology

CABM 010

Tuesday, April 15, 2008
3:00 pm


Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive lysosomal disorders caused by mutations in several distinct genes. Previously, this laboratory identified the gene TPP1 (formerly CLN2) that is mutated in late infantile NCL (LINCL) and its gene product was subsequently determined to be identical to the lysosomal aminopeptidase, tripeptidyl peptidase 1 (TPP-I). The onset of symptoms in LINCL starts at 2 ~ 4 years of age with seizures, and the disease progresses with persistent myoclonic seizures, ataxia, developmental regression and blindness. The median life expectancy of children with LINCL is ~12 years of age. Enzyme replacement, gene and stem cell therapies are under investigation for the treatment of LINCL, but there are currently no proven effective treatment options available. Thus, there remains a need for options to delay the onset of symptoms or to retard the progress of the disease.

TPP-I is expressed ubiquitously throughout the body but pathology appears to be restricted to the brain. One explanation for the absence of peripheral pathology is that in tissues other than brain, other proteases are available to compensate for the loss of TPP-I. One candidate for such a protease is another lysosomal aminopeptidase, dipeptidyl peptidase-I (DPP-I). DPP-I is expressed ubiquitously but its expression level in brain is relatively low compared to peripheral tissues and if DPP-I can substitute for TPP-I, this could explain the lack of peripheral pathology. Compensation for the loss of TPP-I by DPP-I may have therapeutic implications for LINCL and we have investigated this possibility using mouse genetic models. Our rationale was that should DPP-I compensate for the loss of TPP-I in peripheral tissues, then its absence should exacerbate disease in an LINCL mouse model but conversely, increased CNS expression of DPP-I should ameliorate disease. By comparing TPP-I and DPP-I single mutant with a double mutant lacking both proteases, we find that the loss of DPP-I had no effect on accumulation of storage material, disease severity or lifespan of the LINCL mouse. Transgenic expression of DPP-I resulted in a ~2-fold increase in DPP-I activity in the brain but this also failed to have significant effect on survival of the LINCL mouse. These results together indicate that DPP-I cannot functionally compensate for the loss of TPP-I within the brain thus therapeutic approaches aiming to increase neuronal expression of DPP-I appear unlikely to have therapeutic benefits.

LINCL is characterized by progressive neurodegeneration but the cellular pathways leading to cell death remain unknown. It has been suggested that neurons die via apoptosis and anti-apoptotic treatments have been proposed to delay neuronal loss and subsequent progression of LINCL. To investigate the effect of modification of apoptotic pathways in the mouse model of LINCL, p53 null mutant mice and transgenic Bcl-2 mice were generated in TPP-I deficient background. Loss of proapoptotic p53 or increased levels of anti-apoptotic Bcl-2 had no effect on the shortened lifespan of the mutant mice. These results suggest that either neuronal death in LINCL is not apoptotic or that multiple apoptotic pathways are involved in neurodegeneration.


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