Regulation of TPP 1 (CLN2) Activity

描述(由申请人提供)：人类基因CLN2的突变导致神经退行性疾病晚期婴儿神经元蜡样脂褐素沉着症(LINCL)。CLN2编码三肽基肽酶I(TPP I)。人们对TPP I的调控知之甚少，也没有发现内源底物。我的初步数据表明，在盘基网柄菌中，TPP I的活性受APRA和AprB的调节，这是一种调节增殖和发育的分泌因子的组成部分。遗传证据表明，TPP I、N-乙酰氨基葡萄糖基转移酶I(DdGNT4)和与人牙本质涎腺蛋白相似的蛋白质(DdDSPP)是APRA调控的信号转导途径的一部分。我将首先确定APRA和AprB是否在调节TPP I的相同途径中发挥作用。为了检验DdGNT4受TPP I下游APRA和AprB调控的假设，将在TPP I活性低下的细胞中确定DdGNT4的活性。为了验证DdDSPP是APRA/AprB调节的调节TPP I活性的途径的一部分的假设，将在缺乏DdDSPP的细胞中测量TPP I的活性。了解TPP I如何在信号转导通路中发挥作用，可能会导致LINCL治疗方法的发展。

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.