{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T13:10:38Z","timestamp":1772802638467,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T00:00:00Z","timestamp":1540771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010231","name":"Banting Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100010231","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000194","name":"Nova Scotia Health Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000194","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004073","name":"Killam Trusts","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004073","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Despite the increased focus on the role of calcium in the neuronal ceroid lipofuscinoses (NCLs, also known as Batten disease), links between calcium signalling and the proteins associated with the disease remain to be identified. A central protein in calcium signalling is calmodulin (CaM), which regulates many of the same cellular processes affected in the NCLs. In this study, we show that 11 of the 13 NCL proteins contain putative CaM-binding domains (CaMBDs). Many of the missense mutations documented from NCL patients overlap with the predicted CaMBDs and are often key residues of those domains. The two NCL proteins lacking such domains, CLN7 and CLN11, share a commonality in undergoing proteolytic processing by cathepsin L, which contains a putative CaMBD. Since CaM appears to have both direct and indirect roles in the NCLs, targeting it may be a valid therapeutic approach for treating the disease.<\/jats:p>","DOI":"10.3390\/cells7110188","type":"journal-article","created":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T11:10:41Z","timestamp":1540811441000},"page":"188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin"],"prefix":"10.3390","volume":"7","author":[{"given":"Sabateeshan","family":"Mathavarajah","sequence":"first","affiliation":[{"name":"Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danton H.","family":"O\u2019Day","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada"},{"name":"Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Biology, Trent University, Peterborough, ON K9L 0G2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,29]]},"reference":[{"key":"ref_1","first-page":"386","article-title":"Cerebral degeneration with symmetrical changes in the maculae in two members of a family","volume":"23","author":"Batten","year":"1903","journal-title":"Trans. Ophthalmol. Soc. UK"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1177\/0883073813493665","article-title":"Batten disease: Clinical aspects, molecular mechanisms, translational science, and future directions","volume":"28","author":"Dolisca","year":"2013","journal-title":"J. Child Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.bbadis.2013.04.008","article-title":"NCL diseases\u2013clinical perspectives","volume":"1832","author":"Schulz","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s40265-017-0771-8","article-title":"Cerliponase alfa: First global approval","volume":"77","author":"Markham","year":"2017","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.bbadis.2006.05.007","article-title":"Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins","volume":"1762","author":"Lahtinen","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1093\/hmg\/ddy076","article-title":"Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation","volume":"27","author":"Danyukova","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","first-page":"202","article-title":"A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system","volume":"91","author":"Staropoli","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1399-0004.2009.01214.x","article-title":"An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients","volume":"76","author":"Kohan","year":"2009","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5851","DOI":"10.1046\/j.0014-2956.2001.02530.x","article-title":"Elevated lysosomal pH in neuronal ceroid lipofuscinoses (NCLs)","volume":"268","author":"Holopainen","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s00401-015-1512-2","article-title":"Neuronal ceroid lipofuscinosis with DNAJC5\/CSP\u03b1 mutation has PPT1 pathology and exhibit aberrant protein palmitoylation","volume":"131","author":"Henderson","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1203\/pdr.0b013e31802d8a4a","article-title":"Neuronal ceroid lipofuscinosis: A common pathway?","volume":"61","author":"Mousallem","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.bbadis.2006.07.001","article-title":"Diagnosis of the neuronal ceroid lipofuscinoses: An update","volume":"1762","author":"Williams","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1053\/ejpn.2000.0452","article-title":"Batten disease and the control of the Fo subunit c pore by cGMP and calcium","volume":"5","author":"McGeoch","year":"2001","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bosch, M.E., and Kielian, T. (2018). Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities. J. Neurochem., in press.","DOI":"10.1111\/jnc.14545"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.nbd.2007.06.012","article-title":"Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction","volume":"28","author":"Ahtiainen","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"M111.013565","DOI":"10.1074\/mcp.M111.013565","article-title":"LC-MS\/MS analysis of differentially expressed glioblastoma membrane proteome reveals altered calcium signaling and other protein groups of regulatory functions","volume":"11","author":"Polisetty","year":"2012","journal-title":"Mol. Cell. Proteomics."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ceca.2011.08.004","article-title":"Deficient mitochondrial Ca(2+) buffering in the Cln8(mnd) mouse model of neuronal ceroid lipofuscinosis","volume":"50","author":"Kolikova","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/cdd.2008.73","article-title":"HCCS1 overexpression induces apoptosis via cathepsin D and intracellular calcium, and HCCS1 disruption in mice causes placental abnormality","volume":"15","author":"Gan","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.bbrc.2013.04.113","article-title":"Amlodipine prevents apoptotic cell death by correction of elevated intracellular calcium in a primary neuronal model of Batten disease (CLN3 disease)","volume":"436","author":"Warnock","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Huber, R.J., Myre, M.A., and Cotman, S.L. (2014). Loss of Cln3 function in the social amoeba Dictyostelium discoideum causes pleiotropic effects that are rescued by human CLN3. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110544"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1080\/19336918.2016.1236179","article-title":"Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis","volume":"11","author":"Huber","year":"2017","journal-title":"Cell Adh. Migr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10545-016-9986-1","article-title":"Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease","volume":"40","author":"Kwon","year":"2017","journal-title":"J. Inherit Metab. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0092-8674(95)90408-5","article-title":"Calcium signaling","volume":"80","author":"Clapham","year":"1995","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1126\/science.6243188","article-title":"Calmodulin plays a pivotal role in cellular regulation","volume":"207","author":"Cheung","year":"1980","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1096\/fasebj.11.5.9141499","article-title":"Sequence motifs for calmodulin recognition","volume":"11","author":"Rhoads","year":"1997","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1023\/A:1011320027914","article-title":"Calmodulin target database","volume":"1","author":"Yap","year":"2000","journal-title":"J. Struct. Funct. Genomics."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1126\/science.6203171","article-title":"Potentiation of bleomycin lethality by anticalmodulin drugs: A role for calmodulin in DNA repair","volume":"224","author":"Chafouleas","year":"1984","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.bbamcr.2013.10.021","article-title":"The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer","volume":"1843","author":"Berchtold","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1093\/hmg\/ddh321","article-title":"Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway","volume":"13","author":"Luiro","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1080\/14712598.2018.1492544","article-title":"Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses","volume":"18","author":"Donsante","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1016\/j.bbadis.2013.05.014","article-title":"NCL disease mechanisms","volume":"1832","author":"Palmer","year":"2013","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.2174\/1389202054395928","article-title":"What have microarrays told us about the neuronal ceroid lipofuscinoses?","volume":"6","author":"Chan","year":"2005","journal-title":"Curr. Genom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1093\/hmg\/ddh312","article-title":"A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging","volume":"13","author":"Kopra","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"553","DOI":"10.3233\/JAD-142772","article-title":"Calmodulin binding proteins and Alzheimer\u2019s disease","volume":"46","author":"Eshak","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E00011-18","DOI":"10.1128\/MCB.00011-18","article-title":"An Alzheimer\u2019s disease-linked loss-of-function CLN5 variant impairs cathepsin D maturation, consistent with a retromer trafficking defect","volume":"38","author":"Qureshi","year":"2018","journal-title":"Mol. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.bbrc.2004.06.070","article-title":"Calmodulin-binding domains in Alzheimer\u2019s disease proteins: Extending the calcium hypothesis","volume":"320","author":"Myre","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1085\/jgp.201311140","article-title":"Calmodulation meta-analysis: Predicting calmodulin binding via canonical motif clustering","volume":"144","author":"Mruk","year":"2014","journal-title":"J. Gen. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.bbamcr.2010.12.002","article-title":"Calmodulin regulates the non-amyloidogenic metabolism of amyloid precursor protein in platelets","volume":"1813","author":"Canobbio","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9315","DOI":"10.1523\/JNEUROSCI.4808-14.2015","article-title":"The progranulin cleavage products, granulins, exacerbate TDP-43 toxicity and increase TDP-43 levels","volume":"35","author":"Salazar","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1016\/j.bbadis.2012.05.015","article-title":"Proteolytic cleavage of the disease-related lysosomal membrane glycoprotein CLN7","volume":"1822","author":"Steenhuis","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13024-017-0196-6","article-title":"The lysosomal protein cathepsin L is a progranulin protease","volume":"12","author":"Lee","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1515\/BC.2006.112","article-title":"Human cathepsin L rescues the neurodegeneration and lethality in cathepsin B\/L double-deficient mice","volume":"387","author":"Sevenich","year":"2006","journal-title":"Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.bbabio.2010.02.008","article-title":"Role of calcineurin, hnRNPA2 and Akt in mitochondrial respiratory stress-mediated transcription activation of nuclear gene targets","volume":"1797","author":"Guha","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1750-3639.2004.tb00500.x","article-title":"The genetic spectrum of human neuronal ceroid-lipofuscinoses","volume":"14","author":"Mole","year":"2004","journal-title":"Brain Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1097\/NEN.0b013e31816a9e60","article-title":"Protective effects of interrupting the binding of calmodulin to mutant huntingtin","volume":"67","author":"Dudek","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1750-3639.2008.00258.x","article-title":"Neuroprotective effects of calmodulin peptide 76-121aa: Disruption of calmodulin binding to mutant huntingtin","volume":"20","author":"Dudek","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.bbadis.2013.01.009","article-title":"Use of model organisms for the study of neuronal ceroid lipofuscinosis","volume":"1832","author":"Bond","year":"2013","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/7\/11\/188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:26:45Z","timestamp":1760196405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/7\/11\/188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,29]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["cells7110188"],"URL":"https:\/\/doi.org\/10.3390\/cells7110188","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,29]]}}}