{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:34:03Z","timestamp":1789760043112,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Computational techniques for analyzing biological images offer a great potential to enhance our knowledge of the biological processes underlying disorders of the nervous system. Friedreich\u2019s Ataxia (FRDA) is a rare progressive neurodegenerative inherited disorder caused by the low expression of frataxin, which is a small mitochondrial protein. In FRDA cells, the lack of frataxin promotes primarily mitochondrial dysfunction, an alteration of calcium (Ca<jats:sup>2+<\/jats:sup>) homeostasis and the destabilization of the actin cytoskeleton in the neurites and growth cones of sensory neurons. In this paper, a computational multilinear algebra approach was used to analyze the dynamics of the growth cone and its function in control and FRDA neurons. Computational approach, which includes principal component analysis and a multilinear algebra method, is used to quantify the dynamics of the growth cone (GC) morphology of sensory neurons from the dorsal root ganglia (DRG) of the YG8sR humanized murine model for FRDA. It was confirmed that the dynamics and patterns of turning were aberrant in the FRDA growth cones. In addition, our data suggest that other cellular processes dependent on functional GCs such as axonal regeneration might also be affected. Semiautomated computational approaches are presented to quantify differences in GC behaviors in neurodegenerative disease. In summary, the deficiency of frataxin has an adverse effect on the formation and, most importantly, the growth cones\u2019 function in adult DRG neurons. As a result, frataxin deficient DRG neurons might lose the intrinsic capability to grow and regenerate axons properly due to the dysfunctional GCs they build.<\/jats:p>","DOI":"10.3389\/fnmol.2022.912780","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T16:28:18Z","timestamp":1655137698000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Frataxin Deficit Leads to Reduced Dynamics of Growth Cones in Dorsal Root Ganglia Neurons of Friedreich\u2019s Ataxia YG8sR Model: A Multilinear Algebra Approach"],"prefix":"10.3389","volume":"15","author":[{"given":"Diana C.","family":"Mu\u00f1oz-Lasso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Moll\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhon J.","family":"S\u00e1enz-Gamboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Insuasty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"de la Iglesia-Vaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Pook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico V.","family":"Pallard\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Palau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Gonzalez-Cabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00264","article-title":"Calcium deregulation: novel insights to understand Friedreich\u2019s ataxia pathophysiology.","volume":"12","author":"Abeti","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1242\/dmm.018952","article-title":"A novel GAA-repeat-expansion-based mouse model of Friedreich\u2019s ataxia.","volume":"8","author":"Anjomani Virmouni","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"B3","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.conb.2018.02.024","article-title":"Cytoskeleton dynamics in axon regeneration.","volume":"51","author":"Blanquie","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00124","article-title":"Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism.","volume":"8","author":"Bolinches-Amor\u00f3s","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"B5","author":"Brett","year":"2021","journal-title":"Tensor Toolbox for MATLAB<sup>\u00ae<\/sup>, Version 3.2.1."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140959","article-title":"An automated strategy for unbiased morphometric analyses and classifications of growth cones in vitro.","volume":"10","author":"Chitsaz","year":"2015","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/cne.901670203","article-title":"The development of the isthmo-optic tract in the chick, with special reference to the occurrence and correction of developmental errors in the location and connections of isthmo-optic neurons.","volume":"167","author":"Clarke","year":"1976","journal-title":"J. Comp. Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1137\/S0895479896305696","article-title":"A multilinear singular value decomposition.","volume":"21","author":"de Lathauwer","year":"2000","journal-title":"SIAM J. Matrix Anal. Appl."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1016\/j.cub.2010.11.021","article-title":"GDNF acts as a chemoattractant to support ephrinA-induced repulsion of limb motor axons.","volume":"20","author":"Dudanova","year":"2010","journal-title":"Curr. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1046\/j.1460-9568.2002.01892.x","article-title":"GDNF and NGF released by synthetic guidance channels support sciatic nerve regeneration across a long gap.","volume":"15","author":"Fine","year":"2002","journal-title":"Eur J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-51","article-title":"Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor i on neurons.","volume":"7","author":"Franco","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1083\/jcb.103.5.1921","article-title":"Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy.","volume":"103","author":"Goldberg","year":"1986","journal-title":"J. Cell Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1111\/jnc.12303","article-title":"Mitochondrial pathophysiology in Friedreich\u2019s ataxia.","volume":"126","author":"Gonz\u00e1lez-Cabo","year":"2013","journal-title":"J. Neurochem."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0115-7","article-title":"The dynamics of growth cone morphology.","volume":"13","author":"Goodhill","year":"2015","journal-title":"BMC Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1242\/dmm.010900","article-title":"Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich\u2019s ataxia.","volume":"6","author":"Hick","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1093\/jnen\/nly100","article-title":"Intraepidermal nerve fiber density in Friedreich\u2019s ataxia.","volume":"77","author":"Indelicato","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1038\/mt.2016.32","article-title":"Gene transfer of Brain-derived Neurotrophic Factor (BDNF) prevents neurodegeneration triggered by FXN deficiency.","volume":"24","author":"Katsu-Jim\u00e9nez","year":"2016","journal-title":"Mol. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1007\/s12311-017-0860-y","article-title":"Mesenchymal stem cell-derived factors restore function to human frataxin-deficient cells.","volume":"16","author":"Kemp","year":"2017","journal-title":"Cerebellum"},{"key":"B19","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/ana.24846","article-title":"Cytokine therapy-mediated neuroprotection in a Friedreich\u2019s ataxia mouse model.","volume":"81","author":"Kemp","year":"2017","journal-title":"Ann. Neurol."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-016-0326-3","article-title":"Purkinje cell injury, structural plasticity and fusion in patients with friedreich\u2019s ataxia.","volume":"4","author":"Kemp","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1093\/jnen\/nlx087","article-title":"Friedreich ataxia: developmental failure of the dorsal root entry zone.","volume":"76","author":"Koeppen","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1097\/NEN.0000000000000160","article-title":"Friedreich ataxia: failure of GABA-ergic and glycinergic synaptic transmission in the dentate nucleus.","volume":"74","author":"Koeppen","year":"2015","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1159\/000109774","article-title":"Friedreich\u2019s ataxia: an epidemiological study in Valencia, Spain, based on consanguinity analysis.","volume":"14","author":"L\u00f3pez-Arlandis","year":"1995","journal-title":"Neuroepidemiology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240235","article-title":"Synergistic effect of CNTF and GDNF on directed neurite growth in chick embryo dorsal root ganglia.","volume":"15","author":"Mashanov","year":"2020","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1080\/03772063.2019.1615008","article-title":"Multilinear principal component analysis with SVM for disease diagnosis on big data.","volume":"68","author":"Mathew","year":"2019","journal-title":"IETE J. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ceb.2019.12.003","article-title":"Mechanistic advances in axon pathfinding.","volume":"63","author":"McCormick","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/0022-510x(71)90067-0","article-title":"An electrophysiological and pathological study of peripheral nerves in Friedreich\u2019s ataxia.","volume":"12","author":"McLeod","year":"1971","journal-title":"J. Neurol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1001\/archneur.1973.00490250071008","article-title":"Axon outgrowth enhanced by a previous nerve injury.","volume":"29","author":"McQuarrie","year":"1973","journal-title":"Arch. Neurol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/B978-0-12-391857-4.00009-4","article-title":"Methods for cell and particle tracking.","volume":"504","author":"Meijering","year":"2012","journal-title":"Methods Enzymol."},{"key":"B30","first-page":"53","article-title":"Sympathetic nerve fibers ingrowth in the central nervous system of neonatal rodent upon intracerebral NGF injections.","volume":"116","author":"Menesini Chen","year":"1978","journal-title":"Arch. Ital. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1093\/hmg\/ddt576","article-title":"Apoptotic cell death and altered calcium homeostasis caused by frataxin depletion in dorsal root ganglia neurons can be prevented by BH4 domain of Bcl-xL protein.","volume":"23","author":"Mincheva-Tasheva","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1016\/j.neuroimage.2004.03.039","article-title":"Decomposing EEG data into space-time-frequency components using Parallel Factor Analysis.","volume":"22","author":"Miwakeichi","year":"2004","journal-title":"Neuroimage"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00264","article-title":"Reversible axonal dystrophy by calcium modulation in frataxin-deficient sensory neurons of YG8R mice.","volume":"10","author":"Moll\u00e1","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020358","article-title":"Much more than a scaffold: cytoskeletal proteins in neurological disorders.","volume":"9","author":"Mu\u00f1oz-Lasso","year":"","journal-title":"Cells"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-62050-7","article-title":"Cofilin dysregulation alters actin turnover in frataxin-deficient neurons.","volume":"10","author":"Mu\u00f1oz-Lasso","year":"","journal-title":"Sci. Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/ana.1283","article-title":"Small fibers involvement in Friedreich\u2019s ataxia.","volume":"50","author":"Nolano","year":"2001","journal-title":"Ann. Neurol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"18371","DOI":"10.1073\/pnas.0709146104","article-title":"A tensor higher-order singular value decomposition for integrative analysis of DNA microarray data from different studies.","volume":"104","author":"Omberg","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"42588","DOI":"10.1074\/jbc.M301872200","article-title":"Actin glutathionylation increases in fibroblasts of patients with Friedreich\u2019s ataxia: a potential role in the pathogenesis of the disease.","volume":"278","author":"Pastore","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/hmg\/ddw260","article-title":"Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich\u2019s ataxia.","volume":"25","author":"Piermarini","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1093\/brain\/114.2.855","article-title":"Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study","volume":"114","author":"Polo","year":"1991","journal-title":"Brain"},{"key":"B41","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/84818","article-title":"Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits.","volume":"27","author":"Puccio","year":"2001","journal-title":"Nat. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.bbadis.2017.12.005","article-title":"Mitochondrial pore opening and loss of Ca2+ exchanger NCLX levels occur after frataxin depletion.","volume":"1864","author":"Purroy","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B43","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/309791a0","article-title":"Peripheral injury enhances central regeneration of primary sensory neurones.","volume":"309","author":"Richardson","year":"1984","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9080664","article-title":"Antioxidant therapies and oxidative stress in friedreich\u2019s ataxia: The right path or just a diversion?","volume":"9","author":"Rodr\u00edguez","year":"","journal-title":"Antioxidants"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101762","article-title":"Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich\u2019s ataxia model.","volume":"37","author":"Rodr\u00edguez","year":"","journal-title":"Redox Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1136\/jnnp.66.1.93","article-title":"Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich\u2019s ataxia.","volume":"66","author":"Santoro","year":"1999","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/2053-8871-1-10","article-title":"IGF-1 in Friedreich\u2019s Ataxia - proof-of-concept trial.","volume":"1","author":"Sanz-Gallego","year":"2014","journal-title":"Cerebellum Ataxias"},{"key":"B48","doi-asserted-by":"publisher","first-page":"5525","DOI":"10.1523\/JNEUROSCI.5469-08.2009","article-title":"Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide.","volume":"29","author":"Sasaki","year":"2009","journal-title":"J. Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis.","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"B50","doi-asserted-by":"publisher","first-page":"19531","DOI":"10.1073\/pnas.1002171107","article-title":"Glial cell line-derived neurotrophic factor defines the path of developing and regenerating axons in the lateral line system of zebrafish.","volume":"107","author":"Schuster","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B51","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jns.2009.08.052","article-title":"Friedreich\u2019s ataxia: oxidative stress and cytoskeletal abnormalities.","volume":"287","author":"Sparaco","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.neuroscience.2006.06.031","article-title":"Nerve growth factor, glial cell line-derived neurotrophic factor and neurturin prevent semaphorin 3A-mediated growth cone collapse in adult sensory neurons.","volume":"142","author":"Wanigasekara","year":"2006","journal-title":"Neuroscience"},{"key":"B53","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1007\/s40484-019-0186-5","article-title":"A survey of some tensor analysis techniques for biological systems.","volume":"7","author":"Yahyanejad","year":"2019","journal-title":"Quant. Biol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.912780\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T16:28:27Z","timestamp":1655137707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.912780\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,13]]},"references-count":53,"alternative-id":["10.3389\/fnmol.2022.912780"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2022.912780","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,13]]},"article-number":"912780"}}