The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking

References

• Kohlschutter A, Schulz A. Towards understanding the neuronal ceroid lipofuscinoses. BrainDev.31(7), 499–502 (2009).
   Google Scholar
• Jalanko A, Braulke T. Neuronal ceroid lipofuscinoses. Biochim.Biophys.Acta 1793(4), 697–709 (2009).
   Google Scholar
• Mole S, Williams R, Goebel H. TheNeuronal CeroidLipofuscinoses(BattenDisease). (2ndEdition). Oxford University Press, UK (2011). disorder Batten disease. Hum.Mol.Genet. 11(12), 1421–1431 (2002). Comprehensive review of the clinicopathologic features of neuronal ceroid lipofuscinosis (NCL), the spectrum of mutations in each of the NCL genes known at the time of its publication, the genetic models that have been developed for each form of the disease and the proposed functions of each of the proteins encoded by the NCL genes.
   Google Scholar
• Castaneda J, Pearce D. Identification of alpha-fetoprotein as an autoantigen in juvenile Batten disease. Neurobiol.Dis.29(1), 92–102 (2008).
   Google Scholar
• Ostergaard J, Rasmussen T, Molgaard H. Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology76(14), 1245–1251 (2011). First study to closely examine the cardiovascular system in a cohort of genetically defined juvenile-onset NCL (JNCL) patients. Case reports had previously indicated the possibility of cardiac defects in JNCL patients.
   Google Scholar
• Mole S, Williams R, Goebel H. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6(3), 107–126 (2005).
   Google Scholar
• Chattopadhyay S, Ito M, Cooper Jetal. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative
   Google Scholar
• Hofman I, van der Wal A, Dingemans K, Becker A. Cardiac pathology in neuronal ceroid lipofuscinoses – a clinicopathologic correlation in three patients. Eur.J.Paediatr. Neurol.5(Suppl. A), 213–217 (2001).
   Google Scholar
• Lebrun A, Moll-Khosrawi P, Pohl Setal. Analysis of potential biomarkers and modifier genes affecting the clinical course of CLN3 disease. Mol.Med. doi:10.2119/ molmed.2010.00241 (2011) (Epub ahead of print).
   Google Scholar
• Seehafer S, Pearce D. You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiol.Aging27(4), 576–588 (2006).
   Google Scholar
• Bruhn H. A short guided tour through functional and structural features of saposin-like proteins. Biochem.J.389(Pt 2), 249–257 (2005).
   Google Scholar
• Matsuda J, Yoneshige A, Suzuki K. The function of sphingolipids in the nervous system: lessons learnt from mouse models of specific sphingolipid activator protein deficiencies. J.Neurochem.103(Suppl. 1), 32–38 (2007).
   Google Scholar
• Palmer D, Fearnley I, Walker Jetal. Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease). Am.J.Med.Genet.42(4), 561–567 (1992).
   Google Scholar
• Palmer D, Bayliss S, Westlake V. Batten disease and the ATP synthase subunit c turnover pathway: raising antibodies to subunit c. Am. J.Med.Genet.57(2), 260–265 (1995).
   Google Scholar
• Kominami E. What are the requirements for lysosomal degradation of subunit c of mitochondrial ATPase? IUBMBLife54(2), 89–90 (2002).
   Google Scholar
• Ju W, Wronska A, Moroziewicz Detal. Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis (NCLs): genetic predictions from clinical and pathological findings. BeijingDaXueXueBao 38(1), 41–48 (2006).
   Google Scholar
• Tyynela J, Baumann M, Henseler M, Sandhoff K, Haltia M. Sphingolipid activator proteins in the neuronal ceroid-lipofuscinoses: an immunological study. ActaNeuropathol. 89(5), 391–398 (1995).
   Google Scholar
• Lyly A, Von Schantz C, Heine Cetal. Novel interactions of CLN5 support molecular networking between neuronal ceroid lipofuscinosis proteins. BMCCell.Biol.10, 83 (2009).
   Google Scholar
• Persaud-Sawin D-A, Mousallem T, Wang C, Zucker A, Kominami E, Boustany R-M. Neuronal ceroid lipofuscinosis: a common pathway? Pediatr.Res.61(2), 146–152 (2007).
   Google Scholar
• Vesa J, Chin M, Oelgeschlager Ketal. Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Mol.Biol. Cell.13(7), 2410–2420 (2002).
   Google Scholar
• Getty A, Pearce D. Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function. Cell.Mol.LifeSci.68(3), 453–474 (2011).
   Google Scholar
• Kyttala A, Lahtinen U, Braulke T, Hofmann S. Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins. Biochim. Biophys.Acta1762(10), 920–933 (2006).
   Google Scholar
• Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell82(6), 949–957 (1995).
   Google Scholar
• Altschul S, Madden T, Schaffer Aetal. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. NucleicAcidsRes.25(17), 3389–3402 (1997).
   Google Scholar
• Baldwin S, Beal P, Yao S, King A, Cass C, Young J. The equilibrative nucleoside transporter family, SLC29. PflugersArch. 447(5), 735–743 (2004).
   Google Scholar
• Ackley M, Governo R, Cass C, Young J, Baldwin S, King A. Control of glutamatergic neurotransmission in the rat spinal dorsal horn by the nucleoside transporter ENT1. J.Physiol.548(Pt 2), 507–517 (2003).
   Google Scholar
• Pao S, Paulsen I, Saier M Jr. Major facilitator superfamily. Microbiol.Mol.Biol.Rev.62(1), 1–34 (1998).
   Google Scholar
• Nugent T, Mole S, Jones D. The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data. FEBSLett.582(7), 1019–1024 (2008).
   Google Scholar
• Storch S, Pohl S, Quitsch A, Falley K, Braulke T. C-terminal prenylation of the CLN3 membrane glycoprotein is required for efficient endosomal sorting to lysosomes. Traffic8(4), 431–444 (2007).
   Google Scholar
• Siintola E, Topcu M, Aula Netal. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am. J.Hum.Genet.81(1), 136–146 (2007).
   Google Scholar
• Narayan S, Rakheja D, Tan L, Pastor J, Bennett M. CLN3P, the Batten’s disease protein, is a novel palmitoyl-protein Delta-9 desaturase. Ann.Neurol.60(5), 570–577 (2006). Based on a low-homology in silico prediction that CLN3 was a fatty acid desaturase, the authors identified a relatively specific defect in D9 desaturation of palmitoyl groups in extracts from cells with CLN3 deficiency. This raised the possibility that CLN3 may regulate palmitoylated proteins via modulation of the lipid moiety, which is supported by another recent study in Btn1D yeast. However, it is still unclear whether CLN3 plays a direct or indirect role in modulation of palmitoylated proteins.
   Google Scholar
• Narayan S, Tan L, Bennett M. Intermediate levels of neuronal palmitoyl-protein D-9 desaturase in heterozygotes for murine Batten disease. Mol.Genet.Metab.93(1), 89–91 (2008).
   Google Scholar
• Hofmann S, Atashband A, Cho S, Das A, Gupta P, Lu Jy. Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2). Curr. Mol.Med.2(5), 423–437 (2002).
   Google Scholar
• Noskova L, Stranecky V, Hartmannova H etal. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am.J.Hum.Genet. 89(2), 241–252 (2011).
   Google Scholar
• Munroe P, Mitchison H, O’Rawe Aetal. Spectrum of mutations in the Batten disease gene, CLN3. Am.J.Hum.Genet.61(2), 310–316 (1997).
   Google Scholar
• Gachet Y, Codlin S, Hyams J, Mole S. btn1, the Schizosaccharomycespombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis. J.Cell.Sci. 118(Pt 23), 5525–5536 (2005). Describes phenotypes in a new yeast model of JNCL. Using genetic approaches, it was shown that btn1, the yeast CLN3 ortholog, is likely to function in prevacuolar compartments, to regulate post-Golgi sorting into endosomes and lysosomes.
   Google Scholar
• Muzaffar N, Pearce D. Analysis of NCL Proteins from an evolutionary standpoint. Curr.Genom.9(2), 115–136 (2008).
   Google Scholar
• Sarpong A, Schottmann G, Ruther Ketal. Protracted course of juvenile ceroid lipofuscinosis associated with a novel CLN3 mutation (p.Y199X). Clin.Genet.76(1), 38–45 (2009).
   Google Scholar
• Aberg L, Lauronen L, Hamalainen J, Mole S, Autti T. A 30-year follow-up of a neuronal ceroid lipofuscinosis patient with mutations in CLN3 and protracted disease course. Pediatr.Neurol.40(2), 134–137 (2009).
   Google Scholar
• Haskell R, Carr C, Pearce D, Bennett M, Davidson B. Batten disease: evaluation of CLN3 mutations on protein localization and function. Hum.Mol.Genet.9(5), 735–744 (2000).
   Google Scholar
• Golabek A, Kida E, Walus M, Kaczmarski W, Wujek P, Wisniewski K. CLN3 disease process: missense point mutations and protein depletion invitro. Eur.J.Paediatr.Neurol. 5(Suppl. A), 81–88 (2001).
   Google Scholar
• Michalewski M, Kaczmarski W, Golabek A, Kida E, Kaczmarski A, Wisniewski K. Evidence for phosphorylation of CLN3 protein associated with Batten disease. Biochem.Biophys.Res.Commun.253(2), 458–462 (1998).
   Google Scholar
• Ezaki J, Takeda-Ezaki M, Koike Metal. Characterization of Cln3p, the gene product responsible for juvenile neuronal ceroid lipofuscinosis, as a lysosomal integral membrane glycoprotein. J.Neurochem.87(5), 1296–1308 (2003).
   Google Scholar
• Jarvela I, Sainio M, Rantamaki Tetal. Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum.Mol.Genet.7(1), 85–90 (1998).
   Google Scholar
• Kida E, Kaczmarski W, Golabek A, Kaczmarski A, Michalewski M, Wisniewski K. Analysis of intracellular distribution and trafficking of the CLN3 protein in fusion with the green fluorescent protein invitro. Mol.Genet.Metab.66(4), 265–271 (1999).
   Google Scholar
• Kyttala A, Ihrke G, Vesa J, Schell M, Luzio J. Two motifs target Batten disease protein CLN3 to lysosomes in transfected nonneuronal and neuronal cells. Mol.Biol. Cell15, 1313–1323 (2004).
   Google Scholar
• Storch S, Pohl S, Braulke T. A dileucine motif and a cluster of acidic amino acids in the second cytoplasmic domain of the batten disease-related CLN3 protein are required for efficient lysosomal targeting. J.Biol. Chem.279(51), 53625–53634 (2004).
   Google Scholar
• Kyttala A, Yliannala K, Schu P, Jalanko A, Luzio J. AP-1 and AP-3 facilitate lysosomal targeting of Batten disease protein CLN3 via its dileucine motif. J.Biol.Chem.280(11), 10277–10283 (2005).
   Google Scholar
• Oswald M, Palmer D, Damak S. Splicing variants in sheep CLN3, the gene underlying juvenile neuronal ceroid lipofuscinosis. Mol. Genet.Metab.67(2), 169–175 (1999).
   Google Scholar
• Narayan S, Pastor J, Mitchison H, Bennett M. CLN3L, a novel protein related to the Batten disease protein, is overexpressed in Cln3-/- mice and in Batten disease. Brain 127(Pt 8), 1748–1754 (2004).
   Google Scholar
• Ballif B, Hornor S, Jenkins Eetal. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2–p12.2. Nat.Genet. 39(9), 1071–1073 (2007).
   Google Scholar
• Barge-Schaapveld D, Maas S, Polstra A, Knegt L, Hennekam R. The atypical 16p11.2 deletion: a not so atypical microdeletion syndrome? Am.J.Med.Genet.A155A(5), 1066–1072 (2011).
   Google Scholar
• Cotman S, Vrbanac V, Lebel Letal. Cln3Dex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum.Mol. Genet.11(22), 2709–2721 (2002).
   Google Scholar
• Fossale E, Wolf P, Espinola Jetal. Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMCNeurosci.5, 57 (2004).
   Google Scholar
• Cao Y, Staropoli J, Biswas Setal. Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit c accumulation in cerebellar cells. PLoSOne6(2), E17118 (2011).
   Google Scholar
• Chan C, Mitchison H, Pearce D. Transcript and insilico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models. Hum.Mol.Genet.17(21), 3332–3339 (2008).
   Google Scholar
• Kitzmuller C, Haines R, Codlin S, Cutler D, Mole S. A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis. Hum.Mol.Genet.17(2), 303–312 (2008).
   Google Scholar
• Pullarkat R, Morris G. Farnesylation of Batten disease CLN3 protein. Neuropediatrics 28(1), 42–44 (1997).
   Google Scholar
• Persaud-Sawin D, Mcnamara J, Vandongen R, Boustany R. A galactosylceramide binding domain is involved in trafficking of CLN3 from Golgi to rafts via recycling endosomes. Pediatr.Res.56(3), 449–463 (2004).
   Google Scholar
• Cao Y, Espinola J, Fossale Eetal. Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J.Biol.Chem.281(29), 20483–20493 (2006).
   Google Scholar
• Pearce D, Sherman F. A yeast model for the study of Batten disease. Proc.NatlAcad.Sci. USA95(12), 6915–6918 (1998).
   Google Scholar
• Holopainen J, Saarikoski J, Kinnunen P, Jarvela I. Elevated lysosomal pH in neuronal ceroid lipofuscinoses (NCLs). Eur. J.Biochem.268(22), 5851–5856 (2001).
   Google Scholar
• Kim Y, Ramirez-Montealegre D, Pearce D. A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease. Proc.NatlAcad. Sci.USA100(26), 15458–15462 (2003).
   Google Scholar
• Luiro K, Yliannala K, Ahtiainen Letal. Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. Hum.Mol.Genet.13(23), 3017–3027 (2004).
   Google Scholar
• Codlin S, Haines R, Burden J, Mole S. Btn1 affects cytokinesis and cell-wall deposition by independent mechanisms, one of which is linked to dysregulation of vacuole pH. J.Cell. Sci.121(Pt 17), 2860–2870 (2008).
   Google Scholar
• Luiro K, Kopra O, Lehtovirta M, Jalanko A. CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum.Mol.Genet. 10(19), 2123–2131 (2001).
   Google Scholar
• Kovacs A, Weimer J, Pearce D. Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease. Neurobiol. Dis.22(3), 575–585 (2006).
   Google Scholar
• Herrmann P, Druckrey-Fiskaaen C, Kouznetsova Eetal. Developmental impairments of select neurotransmitter systems in brains of Cln3(Deltaex7/8) knock-in mice, an animal model of juvenile neuronal ceroid lipofuscinosis. J.Neurosci. Res.86(8), 1857–1870 (2008).
   Google Scholar
• Finn R, Kovacs A, Pearce D. Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3(Deltaex7/8)-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. Neurochem.Int.58(6), 648–655 (2011).
   Google Scholar
• Uusi-Rauva K, Luiro K, Tanhuanpaa Ketal. Novel interactions of CLN3 protein link Batten disease to dysregulation of fodrin–Na+, K+ ATPase complex. Exp.Cell.Res.314(15), 2895–2905 (2008).
   Google Scholar
• Getty A, Benedict J, Pearce D. A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3-/- cells. Exp.Cell.Res.317(1), 51–69 (2011).
   Google Scholar
• Rakheja D, Narayan S, Pastor J, Bennett M. CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes). Biochem.Biophys.Res.Commun. 317(4), 988–991 (2004).
   Google Scholar
• Chang J, Choi H, Kim Hetal. Neuronal vulnerability of CLN3 deletion to calciuminduced cytotoxicity is mediated by calsenilin. Hum.Mol.Genet.16(3), 317–326 (2007).
   Google Scholar
• Persaud-Sawin D-A, Vandongen A, Boustany R-M. Motifs within the CLN3 protein: modulation of cell growth rates and apoptosis. Hum.Mol.Genet.11(18), 2129–2142 (2002).
   Google Scholar
• Phillips S, Benedict J, Weimer J, Pearce D. CLN3, the protein associated with Batten disease: structure, function and localization. J.Neurosci.Res.79, 573–583 (2005).
   Google Scholar
• De Matteis MA, Luini A. Exiting the Golgi complex. Nat.Rev.Mol.Cell.Biol.9(4), 273–284 (2008).
   Google Scholar
• Wolfe DM, Padilla-Lopez S, Vitiello SP, Pearce DA. pH-dependent localization of Btn1p in the yeast model for Batten disease. Dis.Model.Mech.4(1), 120–125 (2011).
   Google Scholar
• Kama R, Kanneganti V, Ungermann C, Gerst J. The yeast Batten disease ortholog, Btn1, controls endosome–Golgi retrograde transport via SNARE assembly. J.CellBiol. 195(2), 203–215 (2011). Key genetic study in budding yeast, demonstrating that Btn1p, the yeast CLN3 ortholog, functions in the late endosome–Golgi retrograde trafficking pathway. Moreover, it was shown that Btn1p mediates this trafficking pathway by modulating Yck3 (casein kinase II), most likely through its palmitoylation moiety, which in turn regulates SNARE protein assembly, supporting the claim that CLN3 directly or indirectly regulates palmitoylated proteins.
   Google Scholar
• Padilla-Lopez S, Pearce D. Saccharomyces cerevisiae lacking Btn1p modulate vacuolar ATPase activity in order to regulate pH imbalance in the vacuole. J.Biol.Chem. 281(15), 10273–10280 (2006).
   Google Scholar
• Codlin S, Mole SE. S.pombe btn1, the orthologue of the Batten disease gene CLN3, is required for vacuole protein sorting of Cpy1p and Golgi exit of Vps10p. J.Cell.Sci. 122(Pt 8), 1163–1173 (2009).
   Google Scholar
• Metcalf D, Calvi A, Seaman M, Mitchison H, Cutler D. Loss of the Batten disease gene CLN3 prevents exit from the TGN of the mannose 6-phosphate receptor. Traffic9(11), 1905–1914 (2008). Describes evidence that CLN3 deficiency leads to disrupted sorting of the mannose 6-phosphate receptor to lysosomes. This parallels similar findings in yeast models, strengthening the hypothesis that post-Golgi trafficking defects are a key component in JNCL pathogenesis.
   Google Scholar
• Pearce D, Ferea T, Nosel S, Das B, Sherman F. Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nat. Genet.22(1), 55–58 (1999).
   Google Scholar
• Chattopadhyay S, Roberts P, Pearce D. The yeast model for Batten disease: a role for Btn2p in the trafficking of the Golgiassociated vesicular targeting protein, Yif1p. Biochem.Biophys.Res.Commun.302(3), 534–538 (2003).
   Google Scholar
• Kama R, Robinson M, Gerst J. Btn2, a Hook1 ortholog and potential Batten disease-related protein, mediates late endosome–Golgi protein sorting in yeast. Mol.Cell.Biol.27(2), 605–621 (2007).
   Google Scholar
• Nair U, Jotwani A, Geng Jetal. SNARE proteins are required for macroautophagy. Cell146(2), 290–302 (2011).
   Google Scholar
• Behrends C, Sowa M, Gygi S, Harper J. Network organization of the human autophagy system. Nature466(7302), 68–76 (2010).
   Google Scholar
• Yang Z, Klionsky D. An overview of the molecular mechanism of autophagy. Curr. Top.Microbiol.Immunol.335, 1–32 (2009).
   Google Scholar
• Mukaiyama H, Nakase M, Nakamura T, Kakinuma Y, Takegawa K. Autophagy in the fission yeast Schizosaccharomycespombe. FEBS Lett.584(7), 1327–1334 (2010).
   Google Scholar
• Meiringer CT, Auffarth K, Hou H, Ungermann C. Depalmitoylation of Ykt6 prevents its entry into the multivesicular body pathway. Traffic9(9), 1510–1521 (2008).
   Google Scholar
• Koike M, Nakanishi H, Saftig Petal. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J.Neurosci.20(18), 6898–6906 (2000).
   Google Scholar