{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T23:22:01Z","timestamp":1784848921130,"version":"3.55.0"},"reference-count":91,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T00:00:00Z","timestamp":1611446400000},"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 Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer\u2019s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.<\/jats:p>","DOI":"10.3390\/brainsci11020152","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T02:07:00Z","timestamp":1611540420000},"page":"152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias"],"prefix":"10.3390","volume":"11","author":[{"given":"Daisy","family":"Edmison","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swetha","family":"Gowrishankar","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.conb.2018.04.025","article-title":"Converging cellular themes for the hereditary spastic paraplegias","volume":"51","author":"Blackstone","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrn2946","article-title":"Hereditary spastic paraplegias: Membrane traffic and the motor pathway","volume":"12","author":"Blackstone","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s13311-019-00742-3","article-title":"Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration","volume":"16","author":"Peng","year":"2019","journal-title":"Neurotherapeutics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.1172\/JCI77598","article-title":"Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation","volume":"124","author":"Chang","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/acn3.64","article-title":"Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11","volume":"1","author":"Renvoise","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1091\/mbc.e13-03-0170","article-title":"Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15","volume":"24","author":"Hirst","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1212\/NXG.0000000000000098","article-title":"Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)","volume":"2","author":"Hirst","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/mgg3.87","article-title":"AP5Z1\/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia","volume":"2","author":"Schlipf","year":"2014","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1086\/379522","article-title":"Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia","volume":"73","author":"Simpson","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1159\/000443666","article-title":"Loss of Maspardin Attenuates the Growth and Maturation of Mouse Cortical Neurons","volume":"16","author":"Davenport","year":"2016","journal-title":"Neurodegener. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1086\/504927","article-title":"ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia","volume":"79","author":"Mannan","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pantakani, D.V., Czyzewska, M.M., Sikorska, A., Bodda, C., and Mannan, A.U. (2011). Oligomerization of ZFYVE27 (Protrudin) is necessary to promote neurite extension. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029584"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nature14359","article-title":"Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth","volume":"520","author":"Raiborg","year":"2015","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/15548627.2019.1615302","article-title":"Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome","volume":"16","author":"Ivankovic","year":"2020","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/jmg.2010.082263","article-title":"Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability","volume":"48","author":"Helmers","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s13023-017-0721-2","article-title":"Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia","volume":"12","author":"Bettencourt","year":"2017","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/hmg\/ddz310","article-title":"Adaptor protein complex 4 deficiency: A paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking","volume":"29","author":"Behne","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1038\/s41467-018-06172-7","article-title":"AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A","volume":"9","author":"Davies","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"De Pace, R., Skirzewski, M., Damme, M., Mattera, R., Mercurio, J., Foster, A.M., Cuitino, L., Jarnik, M., Hoffmann, V., and Morris, H.D. (2018). Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007363"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E10697","DOI":"10.1073\/pnas.1717327114","article-title":"AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation","volume":"114","author":"Mattera","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.ajhg.2011.04.019","article-title":"Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature","volume":"88","author":"Philippe","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/ng758","article-title":"Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia","volume":"29","author":"Zhao","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1111\/j.1471-4159.2009.06258.x","article-title":"Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum","volume":"110","author":"Muriel","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mcn.2007.01.012","article-title":"Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER\/Golgi interface and Golgi morphogenesis","volume":"35","author":"Namekawa","year":"2007","journal-title":"Mol. Cell Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/15472","article-title":"Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia","volume":"23","author":"Hazan","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1093\/brain\/awv178","article-title":"Hereditary spastic paraplegia SPG4: What is known and not known about the disease","volume":"138","author":"Solowska","year":"2015","journal-title":"Brain"},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1086\/378817","article-title":"NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6)","volume":"73","author":"Rainier","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1097\/NEN.0000000000000000","article-title":"Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model","volume":"72","author":"Watanabe","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1093\/hmg\/ddp324","article-title":"The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling","volume":"18","author":"Tsang","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1086\/510782","article-title":"Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia","volume":"80","author":"Valdmanis","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eaau7500","DOI":"10.1126\/scisignal.aau7500","article-title":"Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion","volume":"13","author":"Lee","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1086\/344210","article-title":"A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)","volume":"71","author":"Reid","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s10048-012-0324-y","article-title":"Axonal transport deficit in a KIF5A(-\/-) mouse model","volume":"13","author":"Karle","year":"2012","journal-title":"Neurogenetics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1177\/1073858412451655","article-title":"Role of kinesin-1 in the pathogenesis of SPG10, a rare form of hereditary spastic paraplegia","volume":"19","author":"Kawaguchi","year":"2013","journal-title":"Neuroscientist"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liu, M., Pi, H., Xi, Y., Wang, L., Tian, L., Chen, M., Xie, J., Deng, P., Zhang, T., and Zhou, C. (2020). KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity. Autophagy, 1\u201322.","DOI":"10.1080\/15548627.2020.1739444"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/ng937","article-title":"SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia","volume":"31","author":"Patel","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.neuron.2012.12.015","article-title":"Spartin regulates synaptic growth and neuronal survival by inhibiting BMP-mediated microtubule stabilization","volume":"77","author":"Nahm","year":"2013","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1086\/505361","article-title":"Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31","volume":"79","author":"Zuchner","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/ana.24488","article-title":"Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum\/mitochondria contacts","volume":"78","author":"Lim","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1172\/JCI65665","article-title":"A spastic paraplegia mouse model reveals REEP1-dependent ER shaping","volume":"123","author":"Beetz","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.ajhg.2013.04.018","article-title":"Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia","volume":"92","author":"Oates","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sambuughin, N., Goldfarb, L.G., Sivtseva, T.M., Davydova, T.K., Vladimirtsev, V.A., Osakovskiy, V.L., Danilova, A.P., Nikitina, R.S., Ylakhova, A.N., and Diachkovskaya, M.P. (2015). Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2. BMC Neurol., 15.","DOI":"10.1186\/s12883-015-0481-3"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1002\/humu.23913","article-title":"Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants","volume":"40","author":"Vulinovic","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1212\/WNL.0b013e3181bacf59","article-title":"SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum","volume":"73","author":"Goizet","year":"2009","journal-title":"Neurology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1093\/brain\/awu121","article-title":"Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48","volume":"137","author":"Pensato","year":"2014","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1136\/jnnp.2008.167528","article-title":"Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia","volume":"80","author":"Schule","year":"2009","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/ng1980","article-title":"Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum","volume":"39","author":"Stevanin","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.ajhg.2008.03.004","article-title":"Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome","volume":"82","author":"Hanein","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3174\/ajnr.A5935","article-title":"\u201cEars of the Lynx\u201d MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia","volume":"40","author":"Pascual","year":"2019","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1212\/WNL.56.9.1230","article-title":"SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q","volume":"56","author":"Hughes","year":"2001","journal-title":"Neurology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Khundadze, M., Kollmann, K., Koch, N., Biskup, C., Nietzsche, S., Zimmer, G., Hennings, J.C., Huebner, A.K., Symmank, J., and Jahic, A. (2013). A hereditary spastic paraplegia mouse model supports a role of ZFYVE26\/SPASTIZIN for the endolysosomal system. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003988"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.mcn.2011.04.004","article-title":"Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia","volume":"47","author":"Murmu","year":"2011","journal-title":"Mol. Cell Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"374","DOI":"10.4161\/auto.27173","article-title":"ZFYVE26\/SPASTIZIN: A close link between complicated hereditary spastic paraparesis and autophagy","volume":"10","author":"Vantaggiato","year":"2014","journal-title":"Autophagy"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E3699","DOI":"10.1073\/pnas.1510329112","article-title":"Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer\u2019s disease amyloid plaques","volume":"112","author":"Gowrishankar","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Varga, R.E., Khundadze, M., Damme, M., Nietzsche, S., Hoffmann, B., Stauber, T., Koch, N., Hennings, J.C., Franzka, P., and Huebner, A.K. (2015). In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005454"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.nbd.2017.02.007","article-title":"Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration","volume":"102","author":"Branchu","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1083\/jcb.201412046","article-title":"Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes","volume":"209","author":"Cheng","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.devcel.2014.06.001","article-title":"Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway","volume":"30","author":"Maday","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1083\/jcb.201106120","article-title":"Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons","volume":"196","author":"Maday","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/tra.12028","article-title":"Adaptor protein complexes AP-4 and AP-5: New players in endosomal trafficking and progressive spastic paraplegia","volume":"14","author":"Hirst","year":"2013","journal-title":"Traffic"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Hirst, J., Barlow, L.D., Francisco, G.C., Sahlender, D.A., Seaman, M.N., Dacks, J.B., and Robinson, M.S. (2011). The fifth adaptor protein complex. PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001170"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hirst, J., Itzhak, D.N., Antrobus, R., Borner, G.H.H., and Robinson, M.S. (2018). Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2004411"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Slabicki, M., Theis, M., Krastev, D.B., Samsonov, S., Mundwiller, E., Junqueira, M., Paszkowski-Rogacz, M., Teyra, J., Heninger, A.K., and Poser, I. (2010). A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000408"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7278","DOI":"10.1074\/jbc.274.11.7278","article-title":"AP-4, a novel protein complex related to clathrin adaptors","volume":"274","author":"Mullins","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1091\/mbc.10.8.2787","article-title":"Characterization of a fourth adaptor-related protein complex","volume":"10","author":"Hirst","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_68","unstructured":"Ebrahimi-Fakhari, D., Behne, R., Davies, A.K., and Hirst, J. (2018). AP-4-Associated Hereditary Spastic Paraplegia. GeneReviews((R)), Oxford University Press."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00439-015-1536-7","article-title":"Delving into the complexity of hereditary spastic paraplegias: How unexpected phenotypes and inheritance modes are revolutionizing their nosology","volume":"134","author":"Tesson","year":"2015","journal-title":"Hum. Genet."},{"key":"ref_70","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Stephens, K., and Amemiya, A. (1993). Hereditary Spastic Paraplegia Overview. GeneReviews((R)), University of Washington."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107837","DOI":"10.1016\/j.celrep.2020.107837","article-title":"Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery","volume":"31","author":"Guardia","year":"2020","journal-title":"Cell Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"12420","DOI":"10.1038\/ncomms12420","article-title":"Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles","volume":"7","author":"Karanasios","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.febslet.2010.01.020","article-title":"New insights into the function of Atg9","volume":"584","author":"Webber","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1083\/jcb.201310021","article-title":"Adaptor proteins involved in polarized sorting","volume":"204","author":"Bonifacino","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_75","first-page":"482","article-title":"Ultrastructural studies in APP\/PS1 mice expressing human ApoE isoforms: Implications for Alzheimer\u2019s disease","volume":"5","author":"Dikranian","year":"2012","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00401-013-1152-3","article-title":"The Alzheimer\u2019s beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques","volume":"126","author":"Kandalepas","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/jnen\/64.2.113","article-title":"Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study","volume":"64","author":"Nixon","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/0006-8993(93)91063-X","article-title":"Identification and distribution of axonal dystrophic neurites in Alzheimer\u2019s disease","volume":"625","author":"Su","year":"1993","journal-title":"Brain Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Drerup, C.M., and Nechiporuk, A.V. (2013). JNK-interacting protein 3 mediates the retrograde transport of activated c-Jun N-terminal kinase and lysosomes. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003303"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1534\/genetics.112.147348","article-title":"An Organelle Gatekeeper Function for Caenorhabditis elegans UNC-16 (JIP3) at the Axon Initial Segment","volume":"194","author":"Edwards","year":"2013","journal-title":"Genetics"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1083\/jcb.201612148","article-title":"Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology","volume":"216","author":"Gowrishankar","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Gowrishankar, S., Lyons, L., Nisha Mohd Rafiq, and Agnes Roczniak-Ferguson, D.C.P.S.M.F (2020). Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. BioRxiv.","DOI":"10.1101\/2020.06.13.149443"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ajhg.2018.12.008","article-title":"De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies","volume":"104","author":"Platzer","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/ana.25481","article-title":"Recurrent de novo MAPK8IP3 variants cause neurological phenotypes","volume":"85","author":"Iwasawa","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: Potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/s41380-019-0396-2","article-title":"Sequential formation of different layers of dystrophic neurites in Alzheimer\u2019s brains","volume":"24","author":"Sharoar","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/WAD.0b013e3181732399","article-title":"Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1","volume":"22","author":"Rudzinski","year":"2008","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nm0498-452","article-title":"A variant of Alzheimer\u2019s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1","volume":"4","author":"Crook","year":"1998","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3109\/00048679509064985","article-title":"Hereditary spastic paraplegia with dementia","volume":"29","author":"Pridmore","year":"1995","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/brain\/121.4.601","article-title":"Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p","volume":"121","author":"Webb","year":"1998","journal-title":"Brain"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Sferra, A., Nicita, F., and Bertini, E. (2020). Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197354"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/2\/152\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:14:46Z","timestamp":1760159686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/2\/152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,24]]},"references-count":91,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["brainsci11020152"],"URL":"https:\/\/doi.org\/10.3390\/brainsci11020152","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,24]]}}}