The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of genetic disorders of neurodegenerative, inflammatory and autoimmune diseases in order to develop novel and rational therapeutic approaches. Towards these goals, the laboratory research of this Section is focused on understanding the regulation and physiological functions of primarily two genes:(1) palmitoyl-protein thioesterase-1 (PPT1) and (2) uteroglobin (UG), also known as Clara cell 10 kDa protein (CC10). Mutations in the PPT1 gene lead to a lethal neurodegenerative storage disorder known as infantile neuronal ceroid lipofuscinosis (INCL). INCL belongs to a group of the most common (1 in 12,500 births) neurodegenerative storage disorders, cumulatively known as Batten disease. Mutations in 8 different genes are reported to cause various forms of Batten disease. There is no effective treatment for any of these diseases. Accordingly, our efforts are focused on understanding the molecular mechanisms of these diseases and to develop rational therapies. Laboratory investigations on INCL have led to a clinical trial, which is currently ongoing. Recently, using PPT1-knockout (PPT1-KO) mice that recapitulate virtually all clinical and pathologic features of INCL, we uncovered for the first time that PPT1-deficiency leads to endoplasmic reticulum (ER) and oxidative stresses leading to neuronal death. In addition we discovered that PPT1-deficiency disrupts synaptic vesicle recycling and causes a progressive decline in the synaptic vesicle (SV) pool, which leads to abnormal neurotransmission, characteristic of INCL. Further, actvation of astroglia leads to neuroinflammation, which contributes to the rapid progression of the disease. The results of our experiments not only provide insight into a complex mechanism of neurodegeneration in INCL but also identifies several potential therapeutic targets. Ongoing studies are attempting to develop novel therapeutic approaches for this disease. Publications: Levin, S.W., Baker, E., Gropman, A., Quezado, Z.M.N., Miao, N., Zhang, Z., Jollands, A., Di Capua, M. and Mukherjee, A.B. (2008) Patients with Infantile Neuronal Ceroid Lipofuscinosis are susceptible to developing Subdural Fluid Collections. Arch. Neurol (in press);Miao N, Levin SW, Baker EH, Caruso RC, Zhang Z, Gropman A, Koziol D, Wesley R, Mukherjee AB, Quezado ZM. (2009) Children with infantile neuronal ceroid lipofuscinosis have an increased risk of hypothermia and bradycardia during anesthesia. Anesth Analg. 109, 372-378.Kim, S.J., Zhang, Z., Lee, Y.C., Sarkar, C., Tsai, P.C., Dye, L. and Mukherjee, A.B. (2008) PPT1-deficiency impairs synaptic vesicle-recycling and regeneration contributing to INCL neuropathology. J. Clin. Invest. 118, 3075-3086.Saha, A., Kim, S.-J., Zhang, Z., Lee, Y.-C., Tsai, P.-C., Soung, J. and Mukherjee, A.B. (2008) Elevated expression of S100B and RAGE mediates neuroinflammation in INCL.FEBS Lett. 582, 3823-3831Chowdhury, B., Zhang, Z., and Mukherjee, A.B. (2008) Uteroglobin interacts with the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation found in IgA-nephropathy. FEBS Lett. 582, 611-615.Wei, H., Kim, S.J., Zhang, Z., Tsai, P.C., Choi, M.S., Wisniewski, K.E. and Mukherjee, A.B. (2008) ER- and oxidative-stresses are common mediators of cellular death in lysosomal storage disorders: Cytoprotective role of chemical chaperones. Hum. Mol. Genet. 17, 469-477.Zhang, Z., Lee, Y.C., Kim, S.J., Choi, M.S., Tsai, P.C., Saha, A., Wei, H, Xu, Y.J., Zhang, P., Heffer, A. and Mukherjee, A.B. (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration.Hum Mol Genet. 16, 837-847.Lee, Y.-C., Zhang, Z., Hitomi, E. and Mukherjee, A.B. (2006). Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett. 580, 4515-4520, 2006. Kim SJ, Zhang Z, Hitomi E, Lee YC and Mukherjee A. B. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.Hum Mol Genet. 15, 1826-1834, 2006. Kim SJ, Zhang Z, Lee YC and Mukherjee AB.(2006) Palmitoyl-protein thioesterase-1deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet. 15,1580-1586, 2006.Zhang Z, Kim SJ, Chowdhury B, Wang J, Lee YC, Tsai PC, Choi M. and Mukherjee AB.Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene. 369, 66-71, 2006.Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A. and Mukherjee AB. (2006). Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum MolGenet. 15, 337-346, 2006.Eisenstein EM, Choi M (2006) Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura. Pediatr Nephrol 21:782-4;Zhang, Z., Kim, S.-J., Lee, Y.-C., Ray, R., Wang, J.-Y., Chowdhury, B., Choi, M.S.,Tsai, P.-C. and Mukherjee, A.B. (2005) Interaction of Uteroglobin with Lipocalin-1 Receptor. Gene. 369:66-71, 2006.Mandal, A.K., Zhang, Z. and Mukherjee, A.B. Yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation. .J. Immunol, Cutting Edge. 75, 6271-6273, 2005.Choi, M. S., Anderson, M.A., Zhang, Z., Zimonjic, D.B., Popescu, N. and Mukherjee, A.B. Neutral ceramidase gene: Role in regulating ceramide-induced apoptosis. (2003) Gene315:113-122;Chandra, S., Davis, J.M., Drexler, S., Kowalewska, J., Koo, H. C., Chester, D., Pollack, S., Welch, R, Pilon, A. and Levine, C.R. (2003) Pediatr Res. (2003)54:509-515;Chowdhury B, Mantile-Selvaggi G, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Lys 43 and Asp 46 in alpha-helix 3 of uteroglobin are essential for its phospholipase A2 inhibitory activity. Biochem Biophys Res Commun. 2002, 295:877-83;Wang CY, Lei HJ, Huang CY, Zhang Z, Mukherjee AB, Yuan CJ. Induction of cyclooxygenase-2 by staurosporine through the activation of nuclear factor for IL-6 (NF-IL6) and activator protein 2 (AP2) in an osteoblast-like cell line. Biochem Pharmacol. 2002 Jul 15;64(2):177-84;Mandal AK, Zhang Z, Chou JY, Mukherjee AB. Pancreatic phospholipase A2 via its receptor regulates expression of key enzymes of phospholipid and sphingolipid metabolism. FASEB J. 2001 Aug;15(10):1834-6. No abstract available. Mandal AK, Zhang Z, Chou JY, Zimonjic D, Keck CL, Popescu N, Mukherjee AB. (2001) Molecular characterization of murine pancreatic phospholipase A(2). DNA Cell Biol.20(3):149-57;Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478-84. Momeda K, Zhang Z, Mukherjee AB, Dhanireddy R. A novel in situ method of SV40 transfection for the establishment of immortal pulmonary alveolartype II cell lines. Ann N Y Acad Sci. 2000;923:325-31. Chowdhury B, Mantile-Selvaggi G, Kundu GC, Miele L, Cordella-Miele E, Zhang Z, Mukherjee AB. Amino acid residues in alpha-helix-3 of human uteroglobin are critical for its phospholipase A2 inhibitory activity. Ann N Y Acad Sci. 2000;923:307-11. Review. No abstract available. Choi M, Zhang Z, Ten Kate LP, Collee JM, Gerritsen J, Mukherjee AB. Human uteroglobin gene polymorphisms and genetic susceptibility to asthma. Ann N Y Acad Sci. 2000;923:303-6. Zhang Z, Kundu GC, Zheng F, Yuan CJ, Lee E, Westphal H, Ward J, DeMayo F, Mukherjee AB. Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann N Y Acad Sci. 2000;923:210-33;
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