EXCEED THE SPACE PROVIDED. The broad, long-term objectives of our studies of Batten disease (BD), the juvenile form of neuronal ceroid lipofuscinosis (NCL), are to understand its molecular pathogenic mechanisms and thus contribute to development of a rational therapy. We have hypothesizcd that: 1) a common metabolic pathway is involved in the pathophysioIogy of NCL including BD, and 2) the pathway is composed of CLN-encoded lysosomal proteinases and a novel transmembrane protein complex that comprisesCLN-encoded proteins including CLNs-encoded Battenin, CLNs- encoded CLN5p, CLN6-encoded CLN@, and CLNg-encoded CLNSp, as well as other unknown protein(s). The specific goal of this application is to study the molecular pathogenic mechanisms of BD by testing our working hypothesis that flzst Battenin-interactive protein (BIp/), a transmembrane protein recently identified in our laboratory, may be involved in BD. BIpr is found to interact not only with Battenin and CLN8p, the normal proteins encoded by the genes CLNs and CLNs, respectively, but also with the mutant Battenim via an increased interactive affinity and with the mutant CLN8pm via a decreased interactive affinity, as well as with mitochondrial ATP synthase (ATPase) subunit C. In addition, our preliminary data suggested that Battenim alters the anti-apoptotic function of BIpr, which is also known as a Bax inhibitor (BI-1), and causes programmed neuronal death in BD. To achieve our goal, four specific aims will be pursued: (1) to explore BIPf interaction with the CLNs- and CLN6- encoded membrane-spanning proteins CLN5p and CLN6p, in addition to CLN_-encoded CLN8p, with the yeast and mammalian two-hybrid systems and immunoprecipitation/pull-down approaches; (2) to characterize the functional relationship of BIPf to BD by determining differential interactions of 'gain/loss-of-affinity' between BIPf and mutant CLN-encoded proteins; (3) to assess the possible roles of BIPfin the pathogenic pathway of BD by testing whether BIPf mediates the pathological accumulation of mitochondrial ATPase subunit C; and (4) to study the regulatory effects of Battenim on the anti-apoptotic function of BIP/in BD. The results of this investigation will lead to pathogenesis of BD. 3ERFORMANCE SITE(S) (organization, city, state) New York State Institute for Basic Research in Staten Island New York KEY PERSONNEL ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Tagle, Danilo A
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Institute for Basic Research in Dev Disabil
Staten Island
United States
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Moroziewicz, Dorota N; Ju, Weina; Zhong, Rocksheng et al. (2006) N-terminal segments are the functional domains of CLN3-encoded battenin for protein interactions. Beijing Da Xue Xue Bao 38:38-40
Ju, Weina; Wronska, Anetta; Moroziewicz, Dorota N et al. (2006) Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis (NCLs): genetic predictions from clinical and pathological findings. Beijing Da Xue Xue Bao 38:41-8
Zhong, Nanbert; Ju, Weina; Moroziewicz, Dorota et al. (2005) Prenatal diagnostic testing for infantile and late-infantile neuronal ceroid lipofusinoses (NCL) using allele specific primer extension (ASPE). Beijing Da Xue Xue Bao 37:20-5
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