{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T03:12:35Z","timestamp":1769829155864,"version":"3.49.0"},"reference-count":46,"publisher":"Portland Press Ltd.","issue":"6","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,12,1]]},"abstract":"<jats:p>Lysosomal diseases are a family of over 50 disorders caused by defects in proteins critical for normal function of the endosomal\/lysosomal system and characterized by complex pathogenic cascades involving progressive dysfunction of many organ systems, most notably the brain. Evidence suggests that compromise in lysosomal function is highly varied and leads to changes in multiple substrate processing and endosomal signalling, in calcium homoeostasis and endoplasmic reticulum stress, and in autophagocytosis and proteasome function. Neurons are highly vulnerable and show abnormalities in perikarya, dendrites and axons, often in ways seemingly unrelated to the primary lysosomal defect. A notable example is NAD (neuroaxonal dystrophy), which is characterized by formation of focal enlargements (spheroids) containing diverse organelles and other components consistent with compromise of retrograde axonal transport. Although neurons may be universally susceptible to NAD, GABAergic neurons, particularly Purkinje cells, appear most vulnerable and ataxia and related features of cerebellar dysfunction are a common outcome. As NAD is found early in disease and thus may be a contributor to Purkinje cell dysfunction and death, understanding its link to lysosomal compromise could lead to therapies designed to prevent its occurrence and thereby ameliorate cerebellar dysfunction.<\/jats:p>","DOI":"10.1042\/bst0381436","type":"journal-article","created":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T15:07:34Z","timestamp":1291216054000},"page":"1436-1441","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Lysosomal compromise and brain dysfunction: examining the role of neuroaxonal dystrophy"],"prefix":"10.1042","volume":"38","author":[{"given":"Steven\u00a0U.","family":"Walkley","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rose F. 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Biochem."},{"key":"2021111909354371500_B4","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10545-008-1040-5","article-title":"Lysosomal diseases: why so complex?","volume":"32","author":"Walkley","year":"2009","journal-title":"J. Inherit. Met. Dis."},{"key":"2021111909354371500_B5","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/acprof:oso\/9780198508786.003.0012","article-title":"Pathogenic cascades and brain dysfunction","volume-title":"Lysosomal Disorders of the Brain","author":"Walkley","year":"2004"},{"key":"2021111909354371500_B6","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ana.410310410","article-title":"Fabry disease: immunocytochemical characterization of neuronal involvement","volume":"31","author":"deVeber","year":"1992","journal-title":"Ann. Neurol."},{"key":"2021111909354371500_B7","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1093\/cercor\/10.10.1028","article-title":"Gangliosides as modulators of dendritogenesis in storage disease-affected and normal pyramidal neurons. Cereb","volume":"10","author":"Walkley","year":"2000","journal-title":"Cortex"},{"key":"2021111909354371500_B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0022-510X(91)90208-O","article-title":"Neuroaxonal dystrophy in neuronal storage disorders: evidence for major GABAergic neuron involvement","volume":"104","author":"Walkley","year":"1991","journal-title":"J. Neurol. Sci."},{"key":"2021111909354371500_B9","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1046\/j.1471-4159.1994.62051852.x","article-title":"Growth of ectopic dendrites on cortical pyramidal neurons in neuronal storage diseases correlates with abnormal accumulation of GM2 ganglioside","volume":"62","author":"Siegel","year":"1994","journal-title":"J. Neurochem."},{"key":"2021111909354371500_B10","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1126\/science.1105681","article-title":"Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease","volume":"307","author":"Stokin","year":"2005","journal-title":"Science"},{"key":"2021111909354371500_B11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0006-8993(86)91348-X","article-title":"Ferric ion\u2013ferrocyanide staining in ganglioside storage disease establishes that meganeurites are of axon hillock origin and distinct from axonal spheroids","volume":"382","author":"Walkley","year":"1986","journal-title":"Brain Res."},{"key":"2021111909354371500_B12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1750-3639.1998.tb00144.x","article-title":"Cellular pathology of lysosomal storage diseases","volume":"8","author":"Walkley","year":"1998","journal-title":"Brain Pathol."},{"key":"2021111909354371500_B13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0074-7742(08)60087-2","article-title":"Pathobiology of neuronal storage disease","volume":"9","author":"Walkley","year":"1988","journal-title":"Int. Rev. Neurobiol."},{"key":"2021111909354371500_B14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1097\/NEN.0b013e3181942cf0","article-title":"Neuropathology of the Mcoln1\u2212\/\u2212 knockout mouse model of mucolipidosis IV","volume":"68","author":"Micsenyi","year":"2009","journal-title":"J. Neuropath. Exp. Neurol."},{"key":"2021111909354371500_B15","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s004010050689","article-title":"Dendritic and axonal abnormalities in feline Niemann\u2013Pick disease type\u00a0C","volume":"94","author":"March","year":"1997","journal-title":"Acta Neuropathol."},{"key":"2021111909354371500_B16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/jnen\/60.1.49","article-title":"Neurons lacking functional NPC1 accumulate gangliosides and cholesterol and undergo dendritic and axonal alterations","volume":"60","author":"Zervas","year":"2001","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2021111909354371500_B17","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/BF00690966","article-title":"Niemann\u2013Pick disease type\u00a0C: study on the nature of the cerebral storage process","volume":"66","author":"Elleder","year":"1985","journal-title":"Acta Neuropathol."},{"key":"2021111909354371500_B18","doi-asserted-by":"crossref","first-page":"5886","DOI":"10.1073\/pnas.0308456101","article-title":"Genetic evidence for non-redundant functional co-operativity between NPC1 and NPC2 in lipid transport","volume":"101","author":"Sleat","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111909354371500_B19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1083\/jcb.84.3.513","article-title":"The movement of membranous organelles in axons: electron microscopic identification of anterogradely and retrogradely transported organelles","volume":"84","author":"Tsukita","year":"1980","journal-title":"J. Cell Biol."},{"key":"2021111909354371500_B20","first-page":"3611","article-title":"Niemann\u2013Pick disease type\u00a0C: a lipid trafficking disorder","volume-title":"The Metabolic and Molecular Bases of Inherited Disease, 8th edn, vol. 3","author":"Patterson","year":"2001"},{"key":"2021111909354371500_B21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.conb.2008.08.005","article-title":"Action in the axon: generation and transport of signaling molecules","volume":"18","author":"Cosker","year":"2008","journal-title":"Curr. Opin. Neurobiol."},{"key":"2021111909354371500_B22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.tcb.2007.09.003","article-title":"Message in a bottle: long-range retrograde signaling in the nervous system","volume":"17","author":"Ib\u00e1\u00f1ez","year":"2007","journal-title":"Trends Cell Biol."},{"key":"2021111909354371500_B23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jprot.2008.10.007","article-title":"The coming of age of axonal neurotrophin signaling endosomes","volume":"72","author":"Wu","year":"2009","journal-title":"J. Proteomics"},{"key":"2021111909354371500_B24","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1002\/dneu.20513","article-title":"Endosomal transport of neurotrophins: roles in signaling and neurodegenerative disease","volume":"67","author":"Bronfman","year":"2007","journal-title":"Dev. Neurobiol."},{"key":"2021111909354371500_B25","first-page":"1094","article-title":"Axonal transport and neurodegenerative disease","volume":"1762","author":"Chevalier-Larsen","year":"2006","journal-title":"Biochem. Biophys. Acta"},{"key":"2021111909354371500_B26","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-004-0952-x","article-title":"Axonal transport defects: a common theme in neurodegenerative diseases","volume":"109","author":"Roy","year":"2005","journal-title":"Acta Neuropathol."},{"key":"2021111909354371500_B27","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1371\/journal.pgen.0020124","article-title":"The genetics of axonal transport and axonal transport disorders","volume":"2","author":"Duncan","year":"2006","journal-title":"PLoS Genet."},{"key":"2021111909354371500_B28","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/cne.903470206","article-title":"Lack of Purkinje cell loss in adult rat cerebellum following protracted axotomy: degenerative changes and regenerative attempts of the severed axons","volume":"347","author":"Dusart","year":"1994","journal-title":"J. Comp. Neurol."},{"key":"2021111909354371500_B29","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.brainresrev.2004.11.007","article-title":"Cell death and axon regeneration of Purkinje cells after axotomy: challenges of classical hypotheses of axon regeneration","volume":"49","author":"Dusart","year":"2005","journal-title":"Brain Res. Rev."},{"key":"2021111909354371500_B30","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1080\/14734220600786444","article-title":"The strange case of Purkinje axon regeneration and plasticity","volume":"5","author":"Rossi","year":"2006","journal-title":"Cerebellum"},{"key":"2021111909354371500_B31","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/cne.10522","article-title":"Patterned Purkinje cell degeneration in mouse models of Niemann\u2013Pick type\u00a0C disease","volume":"456","author":"Sarna","year":"2003","journal-title":"J. Comp. 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Neurol."},{"key":"2021111909354371500_B34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.brainres.2006.07.065","article-title":"The Purkinje cell degeneration (pcd) mouse: an unexpected molecular link between neuronal degeneration and regeneration","volume":"1140","author":"Wang","year":"2007","journal-title":"Brain Res."},{"key":"2021111909354371500_B35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1096\/fj.09-147942","article-title":"CCP1\/Nna1 functions in protein turnover in mouse brain: implications for cell death in Purkinje cell degeneration mice","volume":"24","author":"Berezniuk","year":"2010","journal-title":"FASEB J."},{"key":"2021111909354371500_B36","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1017\/S146239940800080X","article-title":"The pathogenesis of Neimann\u2013Pick C disease: a role for autophagy?","volume":"10","author":"Pacheco","year":"2008","journal-title":"Expert Rev. Mol. Med."},{"key":"2021111909354371500_B37","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1093\/hmg\/ddm289","article-title":"A block of autophagy in lysosomal storage disorders","volume":"17","author":"Settembre","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2021111909354371500_B38","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrn2499","article-title":"Ubiquitin, the proteasome, and protein degradation in neuronal function and dysfunction","volume":"9","author":"Tai","year":"2008","journal-title":"Nat. Neurosci. Rev."},{"key":"2021111909354371500_B39","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1073\/pnas.0602222104","article-title":"Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport","volume":"140","author":"Liu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111909354371500_B40","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1083\/jcb.200306075","article-title":"BPAG1n4 is essential for retrograde axonal transport in sensory neurons","volume":"163","author":"Liu","year":"2003","journal-title":"J. Cell Biol."},{"key":"2021111909354371500_B41","doi-asserted-by":"crossref","first-page":"14489","DOI":"10.1073\/pnas.0701311104","article-title":"Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal regeneration","volume":"104","author":"Komatsu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111909354371500_B42","first-page":"81","article-title":"Cell-autonomous death of cerebellar Purkinje neurons with autophagy in Niemann\u2013Pick type\u00a0C disease","volume":"1","author":"Ko","year":"2005","journal-title":"PLoS Genet."},{"key":"2021111909354371500_B43","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1093\/hmg\/ddp552","article-title":"Conditional Niemann\u2013Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration","volume":"19","author":"Elrick","year":"2010","journal-title":"Hum. Mol. 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