{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:21:08Z","timestamp":1781929268775,"version":"3.54.5"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affecting the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across genotypes despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes.<\/jats:p>","DOI":"10.3390\/brainsci11030403","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T12:55:07Z","timestamp":1616417707000},"page":"403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4446-5371","authenticated-orcid":false,"given":"Alan","family":"Mackay-Sim","sequence":"first","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11910-996-0008-9","article-title":"Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene","volume":"6","author":"Andersen","year":"2006","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.neurol.2017.03.034","article-title":"Hereditary spastic paraplegia: More than an upper motor neuron disease","volume":"173","author":"Parodi","year":"2017","journal-title":"Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1080\/14737175.2019.1608824","article-title":"Hereditary spastic paraplegias: Time for an objective case definition and a new nosology for neurogenetic disorders to facilitate biomarker\/therapeutic studies","volume":"19","author":"Elsayed","year":"2019","journal-title":"Expert Rev. Neurother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s12311-016-0803-z","article-title":"Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks","volume":"16","author":"Bortholin","year":"2017","journal-title":"Cerebellum"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00401-013-1115-8","article-title":"Hereditary spastic paraplegia: Clinico-pathologic features and emerging molecular mechanisms","volume":"126","author":"Fink","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lallemant-Dudek, P., and Durr, A. (2020). Clinical and genetic update of hereditary spastic paraparesis. Rev. Neurol.","DOI":"10.1016\/j.neurol.2020.07.001"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/ana.24611","article-title":"Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients","volume":"79","author":"Schule","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/B978-0-444-64076-5.00041-7","article-title":"Hereditary spastic paraplegia","volume":"148","author":"Blackstone","year":"2018","journal-title":"Handb Clin. Neurol."},{"key":"ref_10","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (2018). Hereditary Spastic Paraplegia Overview. GeneReviews((R)), University of Washington."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/s10038-018-0463-6","article-title":"Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79","volume":"63","author":"Patil","year":"2018","journal-title":"J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1093\/brain\/awz158","article-title":"Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia","volume":"142","author":"Lin","year":"2019","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/s10038-019-0670-9","article-title":"UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes","volume":"64","author":"Nan","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.3174\/ajnr.A3897","article-title":"Brain white matter involvement in hereditary spastic paraplegias: Analysis with multiple diffusion tensor indices","volume":"35","author":"Aghakhanyan","year":"2014","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1148\/radiol.14141715","article-title":"Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage","volume":"276","author":"Agosta","year":"2015","journal-title":"Radiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1002\/mds.23211","article-title":"Specific pattern of early white-matter changes in pure hereditary spastic paraplegia","volume":"25","author":"Duning","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1136\/jnnp-2011-300129","article-title":"White and grey matter abnormalities in patients with SPG11 mutations","volume":"83","author":"Franca","year":"2012","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3109\/00207454.2013.836705","article-title":"Diffusion tensor imaging in SPG11- and SPG4-linked hereditary spastic paraplegia","volume":"124","author":"Garaci","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1007\/s00415-015-7791-7","article-title":"Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations","volume":"262","author":"Lindig","year":"2015","journal-title":"J. Neurol."},{"key":"ref_20","first-page":"181","article-title":"Tract-based spatial statistics of diffusion tensor imaging in hereditary spastic paraplegia with thin corpus callosum reveals widespread white matter changes","volume":"19","author":"Oguz","year":"2013","journal-title":"Diagn Interv. Radiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rezende, T.J., de Albuquerque, M., Lamas, G.M., Martinez, A.R., Campos, B.M., Casseb, R.F., Silva, C.B., Branco, L.M., D\u2019Abreu, A., and Lopes-Cendes, I. (2015). Multimodal MRI-based study in patients with SPG4 mutations. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117666"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1002\/hbm.20971","article-title":"Whole brain-based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging","volume":"31","author":"Unrath","year":"2010","journal-title":"Hum. Brain Mapp."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Martinuzzi, A., Montanaro, D., Vavla, M., Paparella, G., Bonanni, P., Musumeci, O., Brighina, E., Hlavata, H., Rossi, G., and Aghakhanyan, G. (2016). Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153283"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Servelhere, K.R., Rezende, T.J.R., de Lima, F.D., de Brito, M.R., de Franca Nunes, R.F., Casseb, R.F., Pedroso, J.L., Barsottini, O.G.P., Cendes, F., and Franca, M.C. (2021). Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes. Mov. Disord.","DOI":"10.1002\/mds.28519"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Servelhere, K.R., Casseb, R.F., de Lima, F.D., Rezende, T.J.R., Ramalho, L.P., and Franca, M.C. (2021). Spinal Cord Gray and White Matter Damage in Different Hereditary Spastic Paraplegia Subtypes. AJNR Am. J. Neuroradiol.","DOI":"10.3174\/ajnr.A7017"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1007\/s00234-005-1415-3","article-title":"Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia","volume":"47","author":"Hedera","year":"2005","journal-title":"Neuroradiology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"508","DOI":"10.3389\/fneur.2019.00508","article-title":"Are Cognitive Changes in Hereditary Spastic Paraplegias Restricted to Complicated Forms?","volume":"10","author":"Ayres","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_28","first-page":"489","article-title":"A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations","volume":"6","author":"Abrahamsen","year":"2013","journal-title":"Dis. Model Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1093\/hmg\/ddt101","article-title":"A patient-derived olfactory stem cell disease model for ataxia-telangiectasia","volume":"22","author":"Stewart","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1242\/dmm.005447","article-title":"Disease-specific, neurosphere-derived cells as models for brain disorders","volume":"3","author":"Matigian","year":"2010","journal-title":"Dis. Model Mech."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cook, A.L., Vitale, A.M., Ravishankar, S., Matigian, N., Sutherland, G.T., Shan, J., Sutharsan, R., Perry, C., Silburn, P.A., and Mellick, G.D. (2011). NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson\u2019s disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021907"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27004","DOI":"10.1038\/srep27004","article-title":"Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia","volume":"6","author":"Wali","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3389\/fnins.2020.00401","article-title":"Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons","volume":"14","author":"Wali","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.1471-4159.2009.06104.x","article-title":"Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients","volume":"110","author":"Kasher","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/stem.1569","article-title":"Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia","volume":"32","author":"Denton","year":"2014","journal-title":"Stem. Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9615","DOI":"10.1038\/s41598-019-45246-4","article-title":"Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons","volume":"9","author":"Rehbach","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1093\/hmg\/ddt644","article-title":"Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients\u2019 neurons","volume":"23","author":"Havlicek","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., and Amemiya, A. (1993). Spastic Paraplegia 7. GeneReviews((R)), University of Washington."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S0092-8674(00)81203-9","article-title":"Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease","volume":"93","author":"Casari","year":"1998","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1172\/JCI200420138","article-title":"Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport","volume":"113","author":"Ferreirinha","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"820","DOI":"10.3389\/fnins.2020.00820","article-title":"Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells","volume":"14","author":"Wali","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/humu.20682","article-title":"A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia","volume":"29","author":"Arnoldi","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1083\/jcb.200304112","article-title":"Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia","volume":"163","author":"Atorino","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/hmg\/ddi447","article-title":"Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners","volume":"15","author":"Sanderson","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-neuro-062111-150400","article-title":"Cellular pathways of hereditary spastic paraplegia","volume":"35","author":"Blackstone","year":"2012","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5638","DOI":"10.1093\/hmg\/ddu280","article-title":"Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A","volume":"23","author":"Zhu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1002\/1873-3468.12702","article-title":"Liver X receptors link lipid metabolism and inflammation","volume":"591","author":"Schulman","year":"2017","journal-title":"FEBS Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1111\/j.1742-4658.2011.08432.x","article-title":"Cytochrome P450s in the synthesis of cholesterol and bile acids--from mouse models to human diseases","volume":"279","author":"Lorbek","year":"2012","journal-title":"FEBS J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16536","DOI":"10.1074\/jbc.M001811200","article-title":"Disruption of the oxysterol 7alpha-hydroxylase gene in mice","volume":"275","author":"Lund","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1194\/jlr.M002543","article-title":"Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis","volume":"51","author":"Schule","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/ana.24633","article-title":"GSK3ss-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model","volume":"79","author":"Mishra","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1093\/hmg\/ddu200","article-title":"Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia","volume":"23","author":"Mishra","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"914","DOI":"10.3389\/fnins.2018.00914","article-title":"Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons","volume":"12","author":"Pozner","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.neuroscience.2008.01.070","article-title":"Decreased expression of the mitochondrial matrix proteases Lon and ClpP in cells from a patient with hereditary spastic paraplegia (SPG13)","volume":"153","author":"Hansen","year":"2008","journal-title":"Neuroscience"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1093\/hmg\/ddy156","article-title":"Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias","volume":"27","author":"Denton","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ygeno.2006.04.003","article-title":"A systematic analysis of human CHMP protein interactions: Additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex","volume":"88","author":"Tsang","year":"2006","journal-title":"Genomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3389\/fnins.2018.00084","article-title":"Steroid Transport, Local Synthesis, and Signaling within the Brain: Roles in Neurogenesis, Neuroprotection, and Sexual Behaviors","volume":"12","author":"Diotel","year":"2018","journal-title":"Front Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.bbapap.2010.06.021","article-title":"At the crossroads of steroid hormone biosynthesis: The role, substrate specificity and evolutionary development of CYP17","volume":"1814","author":"Gilep","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1146\/annurev-biochem-072711-163501","article-title":"Form follows function: The importance of endoplasmic reticulum shape","volume":"84","author":"Westrate","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nrm.2015.8","article-title":"Structure and function of ER membrane contact sites with other organelles","volume":"17","author":"Phillips","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1083\/jcb.201211045","article-title":"An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome","volume":"202","author":"Allison","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1172\/JCI60560","article-title":"Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12","volume":"122","author":"Montenegro","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/tra.12715","article-title":"Life in the lumen: The multivesicular endosome","volume":"21","author":"Gruenberg","year":"2020","journal-title":"Traffic"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Li, L., Tong, M., Fu, Y., Chen, F., Zhang, S., Chen, H., Ma, X., Li, D., Liu, X., and Zhong, Q. (2020). Lipids and membrane-associated proteins in autophagy. Protein Cell.","DOI":"10.1007\/s13238-020-00793-9"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"158544","DOI":"10.1016\/j.bbalip.2019.158544","article-title":"ER morphology and endo-lysosomal crosstalk: Functions and disease implications","volume":"1865","author":"Lee","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1083\/jcb.201609033","article-title":"Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia","volume":"216","author":"Allison","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/brain\/awz382","article-title":"Lipid metabolic pathways converge in motor neuron degenerative diseases","volume":"143","author":"Rickman","year":"2020","journal-title":"Brain"},{"key":"ref_69","first-page":"5111","article-title":"Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation","volume":"25","author":"Renvoise","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Papadopoulos, C., Orso, G., Mancuso, G., Herholz, M., Gumeni, S., Tadepalle, N., Jungst, C., Tzschichholz, A., Schauss, A., and Honing, S. (2015). Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005149"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Arribat, Y., Grepper, D., Lagarrigue, S., Qi, T., Cohen, S., and Amati, F. (2020). Spastin mutations impair coordination between lipid droplet dispersion and reticulum. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008665"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1083\/jcb.201902061","article-title":"Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III","volume":"218","author":"Chang","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1242\/bio.20147641","article-title":"Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia","volume":"3","author":"Fan","year":"2014","journal-title":"Biol. Open"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.stem.2018.12.013","article-title":"Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-beta in iPSC-Derived Alzheimer\u2019s Disease Neurons","volume":"24","author":"Langness","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nrd4280","article-title":"Liver X receptors in lipid metabolism: Opportunities for drug discovery","volume":"13","author":"Hong","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/jcb.21006","article-title":"Nuclear localization of liver X receptor alpha and beta is differentially regulated","volume":"100","author":"Prufer","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.mcn.2016.01.001","article-title":"The GSK3-MAP1B pathway controls neurite branching and microtubule dynamics","volume":"72","author":"Barnat","year":"2016","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s42003-019-0615-z","article-title":"Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis","volume":"2","author":"Boutry","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.devcel.2017.02.020","article-title":"The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species","volume":"40","author":"Bordt","year":"2017","journal-title":"Dev. Cell."},{"key":"ref_80","first-page":"9741369","article-title":"Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule","volume":"2020","author":"Wang","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.expneurol.2011.06.003","article-title":"Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis","volume":"231","author":"Yoo","year":"2011","journal-title":"Exp. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/med.21528","article-title":"Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs","volume":"39","author":"Jaiswal","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"23465","DOI":"10.1074\/jbc.M703434200","article-title":"Stabilization of hyperdynamic microtubules is neuroprotective in amyotrophic lateral sclerosis","volume":"282","author":"Fanara","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Perlman, S.L. (2020). Update on the Treatment of Ataxia: Medication and Emerging Therapies. Neurotherapeutics.","DOI":"10.1007\/s13311-020-00941-3"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1093\/brain\/awv008","article-title":"Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration","volume":"138","author":"Medard","year":"2015","journal-title":"Brain"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1093\/hmg\/ddw220","article-title":"Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling","volume":"25","author":"Gregianin","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2007.08.036","article-title":"Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival","volume":"131","author":"Hayashi","year":"2007","journal-title":"Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"16158","DOI":"10.1038\/s41598-017-16488-x","article-title":"Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells","volume":"7","author":"Panagaki","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1074\/jbc.RA118.005683","article-title":"Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell","volume":"294","author":"Yamamoto","year":"2019","journal-title":"J. Biol. Chem."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/3\/403\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:25Z","timestamp":1760161165000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/3\/403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,22]]},"references-count":89,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["brainsci11030403"],"URL":"https:\/\/doi.org\/10.3390\/brainsci11030403","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,22]]}}}