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 hypothesized that: 1) a common metabolic pathway is involved in the pathophysiology of a NCL including BD, and 2) the pathway is composed of CLN-encoded lysosomal proteinases and a novel transmembrane protein complex that comprises CLN-encoded proteins including CLN3-encoded Battenin, CLN5-encoded CLN5p, CLN6-encoded CLN6p, and CLN8-encoded CLN8p, 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 fast Battenin-interactive protein (BIPf), a transmembrane protein recently identified in our laboratory, may be involved in BD. BIPf is found to interact not only with Battenin and CLN8p, the normal proteins encoded by the genes CLN3 and CLN8, respectively, but also with the mutant Battenin 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 BIPf, 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 CLN5-and CLN6-encoded membrane-spanning proteins CLN5p and CLN6p, in addition to CLN6-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 BIPf in the pathogenic pathway of BD by testing whether BIPf medicates the pathological accumulation of mitochondrial ATPase subunit C; and (4) to study the regulatory effects of Battenim on the anti-apoptotic function of BIPf in BD. The results of this investigation will lead to a better understanding of the molecular mechanisms underlying the pathogenesis of BD.
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