Regulation of TPP 1 (CLN2) Activity

Rice University, Houston TX

Investigators

Abstract

DESCRIPTION (provided by applicant): Mutations in the human gene CLN2 cause the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis (LINCL). CLN2 encodes the protease tripeptidyl peptidase I (TPP I). Little is known about the regulation of TPP I and no endogenous substrates have been identified. My preliminary data indicate that in Dictyostelium discoideum TPP I activity is regulated by AprA and AprB, components of a secreted factor that regulates proliferation and development. Genetic evidence indicates that TPP I, an N- acetylglucosaminyltransferase I (DdGNT4), and a protein with similarity to human dentin sialophoshoprotein (DdDSPP) are part of a signal transduction pathway regulated by AprA. I will first determine if AprA and AprB function in the same pathway to regulate TPP I. To test the hypothesis that DdGNT4 is regulated by AprA and AprB downstream of TPP I, DdGNT4 activity will be determined in cells with deficient TPP I activity. To test the hypothesis that DdDSPP is part of the AprA/AprB regulated pathway that regulates TPP I activity, TPP I activity will be measured in cells that lack DdDSPP. Understanding how TPP I functions in a signal transduction pathway may lead to the development of treatments for LINCL.