SCA34 caused by ELOVL4 L168F mutation is a lysosomal lipid storage disease sharing pathology features with neuronal ceroid lipofuscinosis and peroxisomal disorders.
Autopsy
Electron microscopy
Lysosomal storage diseases
Microglia
Spinocerebellar ataxia
Very long-chain fatty acids
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
16
03
2023
accepted:
27
04
2023
revised:
27
04
2023
medline:
10
7
2023
pubmed:
15
5
2023
entrez:
15
5
2023
Statut:
ppublish
Résumé
Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain fatty acids (VLCFAs). We performed post-mortem neuropathological examinations on four SCA34 patients with the ELOVL4 L168F mutation and compared the findings to age-matched controls. Specific gross findings of SCA34 were limited to pontocerebellar atrophy. On light microscopy, pontine base showed neuronal loss and storage of an autofluorescent lipopigment positive on oil red O, PAS and Hale's colloidal iron and negative on Alcian blue and Luxol fast blue (LFB). Among the swollen neurons were abundant CD68+ /CD163+ /IBA1- macrophages laden with a material with similar histochemical profile as in neurons except for the lack of autofluorescence and oil red O positivity and the presence of needle-like birefringent inclusions. Normal resting IBA1 + microglia were generally absent from pontine base nuclei but present in normal numbers elsewhere in the pons. In dentate nucleus neurons, atrophy was milder than in the pontine base and the coarser storage material was LFB-positive, closely resembling lipofuscin. On electron microscopy, dentate nucleus neurons showed neuronal storage of tridimensionally organized trilaminar spicules within otherwise normal lipofuscin, while in the more affected pontine base neurons, lipofuscin was almost completely replaced by the storage material. Storage macrophages were tightly packed with stacks of unorganized trilaminar spicules, reminiscent of the storage material seen in peroxisomal disorders and thought to represent VLCFAs incorporated in complex polar lipids. In summary, we provide histochemical and ultrastructural evidence that SCA34 is a lipid storage disease, the first among the currently known SCAs, and that the storage lipid is accumulating within neuronal lipofuscin. Our findings suggest that the storage lipid is similar to the one accumulating in non-neuronal cells in peroxisomal disorders and provide the first ultrastructural description of this type of material within neurons.
Identifiants
pubmed: 37184663
doi: 10.1007/s00401-023-02582-0
pii: 10.1007/s00401-023-02582-0
doi:
Substances chimiques
oil red O
G7S71FND9B
Lipofuscin
0
Lipids
0
ELOVL4 protein, human
0
Eye Proteins
0
Membrane Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
337-352Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Adams CW, Bayliss OB (1968) Histochemistry of myelin. VII. Analysis of lipid-protein relationships and absence of acid mucopolysaccharide. J Histochem Cytochem 16:119–127. https://doi.org/10.1177/16.2.119
doi: 10.1177/16.2.119
pubmed: 4171735
Agbaga MP, Brush RS, Mandal MN, Henry K, Elliott MH, Anderson RE (2008) Role of stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci U S A 105:12843–12848. https://doi.org/10.1073/pnas.0802607105
doi: 10.1073/pnas.0802607105
pubmed: 18728184
pmcid: 2525561
Aldahmesh MA, Mohamed JY, Alkuraya HS, Verma IC, Puri RD, Alaiya AA et al (2011) Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89:745–750. https://doi.org/10.1016/j.ajhg.2011.10.011
doi: 10.1016/j.ajhg.2011.10.011
pubmed: 22100072
pmcid: 3234380
Anderson G, Elleder M, Goebel HH (2011) Morphological Diagnostic and Pathological Considerations. In: Mole SE, Williams RE, Goebel HH (eds) The neuronal ceroid lipofuscinoses (batten disease), 2nd edn. Oxford University Press, New York, pp 35–49
doi: 10.1093/med/9780199590018.003.0004
Beaudin M, Sellami L, Martel C, Touzel-Deschenes L, Houle G, Martineau L et al (2020) Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34. Neurol Genet 6:e403. https://doi.org/10.1212/NXG.0000000000000403
doi: 10.1212/NXG.0000000000000403
pubmed: 32211516
pmcid: 7073455
Bergner CG, van der Meer F, Winkler A, Wrzos C, Turkmen M, Valizada E et al (2019) Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Glia 67:1196–1209. https://doi.org/10.1002/glia.23598
doi: 10.1002/glia.23598
pubmed: 30980503
pmcid: 6594046
Bhattacharjee S, Jun B, Belayev L, Heap J, Kautzmann MA, Obenaus A et al (2017) Elovanoids are a novel class of homeostatic lipid mediators that protect neural cell integrity upon injury. Sci Adv 3:e1700735. https://doi.org/10.1126/sciadv.1700735
doi: 10.1126/sciadv.1700735
pubmed: 28959727
pmcid: 5617374
Blinkov SM, Glezer II (1968) Human brain in figures and tables. A quantitative handbook. Plenum Press, New York
Bourassa CV, Raskin S, Serafini S, Teive HA, Dion PA, Rouleau GA (2015) A new ELOVL4 mutation in a case of spinocerebellar ataxia with erythrokeratodermia. JAMA Neurol 72:942–943. https://doi.org/10.1001/jamaneurol.2015.0888
doi: 10.1001/jamaneurol.2015.0888
pubmed: 26258735
Bourque PR, Warman-Chardon J, Lelli DA, LaBerge L, Kirshen C, Bradshaw SH et al (2018) Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34). Neurol Genet 4:e263. https://doi.org/10.1212/NXG.0000000000000263
doi: 10.1212/NXG.0000000000000263
pubmed: 30065956
pmcid: 6066365
Cadieux-Dion M, Turcotte-Gauthier M, Noreau A, Martin C, Meloche C, Gravel M et al (2014) Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol 71:470–475. https://doi.org/10.1001/jamaneurol.2013.6337
doi: 10.1001/jamaneurol.2013.6337
pubmed: 24566826
Cameron DJ, Tong Z, Yang Z, Kaminoh J, Kamiyah S, Chen H et al (2007) Essential role of Elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival. Int J Biol Sci 3:111–119. https://doi.org/10.7150/ijbs.3.111
doi: 10.7150/ijbs.3.111
pubmed: 17304340
pmcid: 1796949
Chausse B, Kakimoto PA, Kann O (2021) Microglia and lipids: how metabolism controls brain innate immunity. Semin Cell Dev Biol 112:137–144. https://doi.org/10.1016/j.semcdb.2020.08.001
doi: 10.1016/j.semcdb.2020.08.001
pubmed: 32807643
Clark HB (2015) Degenerative Disorders. In: Love S, Budka H, Ironside JW, Perry A (eds) Greenfield’s neuropathology. CRC Press, Boca Raton, FL, pp 79–816
Depreter M, Espeel M, Roels F (2003) Human peroxisomal disorders. Microsc Res Tech 61:203–223. https://doi.org/10.1002/jemt.10330
doi: 10.1002/jemt.10330
pubmed: 12740827
Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N et al (2014) ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet 95:209–217. https://doi.org/10.1016/j.ajhg.2014.07.001
doi: 10.1016/j.ajhg.2014.07.001
pubmed: 25065913
pmcid: 4129408
Dingemans KP, Mooi WJ, van den Bergh Weerman MA (1983) Angulate lysosomes. Ultrastruct Pathol 5:113–122. https://doi.org/10.3109/01913128309141830
doi: 10.3109/01913128309141830
pubmed: 6199876
Eichler FS, Ren JQ, Cossoy M, Rietsch AM, Nagpal S, Moser AB et al (2008) Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 63:729–742. https://doi.org/10.1002/ana.21391
doi: 10.1002/ana.21391
pubmed: 18571777
Faust PL, Powers JM (2015) Peroxisomal Disorders. In: Love S, Budka H, Ironside JW, Perry A (eds) Greenfield’s neuropathology. CRC Press, Boca Raton, FL, pp 562–588
Fiorenza MT, Moro E, Erickson RP (2018) The pathogenesis of lysosomal storage disorders: beyond the engorgement of lysosomes to abnormal development and neuroinflammation. Hum Mol Genet 27:R119–R129. https://doi.org/10.1093/hmg/ddy155
doi: 10.1093/hmg/ddy155
pubmed: 29718288
Francelle L, Mazzulli JR (2022) Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson’s disease. Brain Res 1780:147798. https://doi.org/10.1016/j.brainres.2022.147798
doi: 10.1016/j.brainres.2022.147798
pubmed: 35063468
pmcid: 9126024
Garcia LM, Hacker JL, Sase S, Adang L, Almad A (2020) Glial cells in the driver seat of leukodystrophy pathogenesis. Neurobiol Dis 146:105087. https://doi.org/10.1016/j.nbd.2020.105087
doi: 10.1016/j.nbd.2020.105087
pubmed: 32977022
Giroux JM, Barbeau A (1972) Erythrokeratodermia with ataxia. Arch Dermatol 106:183–188
doi: 10.1001/archderm.1972.01620110019005
pubmed: 5048218
Goebel HH, Busch H (1989) Abnormal lipopigments and lysosomal residual bodies in metachromatic leukodystrophy. Adv Exp Med Biol 266:299–309. https://doi.org/10.1007/978-1-4899-5339-1_21
doi: 10.1007/978-1-4899-5339-1_21
pubmed: 2486156
Gray DA, Woulfe J (2005) Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowl Environ 2005:1–5. https://doi.org/10.1126/sageke.2005.5.re1
doi: 10.1126/sageke.2005.5.re1
Gyening YK, Chauhan NK, Tytanic M, Ea V, Brush RS, Agbaga MP (2022) ELOVL4 mutations that cause spinocerebellar ataxia-34 differentially alter very long chain fatty acid biosynthesis. J Lipid Res 64:100317. https://doi.org/10.1016/j.jlr.2022.100317
doi: 10.1016/j.jlr.2022.100317
pubmed: 36464075
pmcid: 9823237
Hopiavuori BR, Anderson RE, Agbaga MP (2019) ELOVL4: very long-chain fatty acids serve an eclectic role in mammalian health and function. Prog Retin Eye Res 69:137–158. https://doi.org/10.1016/j.preteyeres.2018.10.004
doi: 10.1016/j.preteyeres.2018.10.004
pubmed: 30982505
Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P et al (2007) Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39:1434–1436. https://doi.org/10.1038/ng.2007.43
doi: 10.1038/ng.2007.43
pubmed: 18037885
Hoxha E, Gabriele RMC, Balbo I, Ravera F, Masante L, Zambelli V et al (2017) Motor deficits and cerebellar atrophy in Elovl5 knock out mice. Front Cell Neurosci 11:343. https://doi.org/10.3389/fncel.2017.00343
doi: 10.3389/fncel.2017.00343
pubmed: 29163054
pmcid: 5670146
Huang M, Verbeek DS (2019) Why do so many genetic insults lead to Purkinje cell degeneration and spinocerebellar ataxia? Neurosci Lett 688:49–57. https://doi.org/10.1016/j.neulet.2018.02.004
doi: 10.1016/j.neulet.2018.02.004
pubmed: 29421540
Jellinger K, Anzil AP, Seemann D, Bernheimer H (1982) Adult GM2 gangliosidosis masquerading as slowly progressive muscular atrophy: motor neuron disease phenotype. Clin Neuropathol 1:31–44
pubmed: 7166018
Johnson AB, Schaumburg HH, Powers JM (1976) Histochemical characteristics of the striated inclusions of adrenoleukodystrophy. J Histochem Cytochem 24:725–730. https://doi.org/10.1177/24.6.59773
doi: 10.1177/24.6.59773
pubmed: 59773
Karan G, Lillo C, Yang Z, Cameron DJ, Locke KG, Zhao Y et al (2005) Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proc Natl Acad Sci USA 102:4164–4169. https://doi.org/10.1073/pnas.0407698102
doi: 10.1073/pnas.0407698102
pubmed: 15749821
pmcid: 554798
Kelley RI, Datta NS, Dobyns WB, Hajra AK, Moser AB, Noetzel MJ et al (1986) Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes. Am J Med Genet 23:869–901. https://doi.org/10.1002/ajmg.1320230404
doi: 10.1002/ajmg.1320230404
pubmed: 3515938
Kerckaert I, Dingemans KP, Heymans HS, Vamecq J, Roels F (1988) Polarizing inclusions in some organs of children with congenital peroxisomal diseases (Zellweger’s, Refsum’s, chondrodysplasia punctata (rhizomelic form), X-linked adrenoleukodystrophy). J Inherit Metab Dis 11:372–386. https://doi.org/10.1007/BF01800426
doi: 10.1007/BF01800426
pubmed: 2468818
Lindboe CF (2003) Brain weight: what does it mean? Clin Neuropathol 22:263–265
pubmed: 14672503
Lowden JA, Callahan JW, Gravel RA, Skomorowski MA, Becker L, Groves J (1981) Type 2 GM1 gangliosidosis with long survival and neuronal ceroid lipofuscinosis. Neurology 31:719–724. https://doi.org/10.1212/wnl.31.6.719
doi: 10.1212/wnl.31.6.719
pubmed: 6787458
Lycette RM, Danforth WF, Koppel JL, Olwin JH (1970) The binding of luxol fast blue ARN by various biological lipids. Stain Technol 45:155–160. https://doi.org/10.3109/10520297009067471
doi: 10.3109/10520297009067471
pubmed: 4316713
Michaud J, Giroux JM (2001) Erythrokératodermie avec ataxie: première étude neuropathologique. Revue Neurol 157:327
Moon YA, Hammer RE, Horton JD (2009) Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res 50:412–423. https://doi.org/10.1194/jlr.M800383-JLR200
doi: 10.1194/jlr.M800383-JLR200
pubmed: 18838740
pmcid: 2638104
Moser HW, Moser AB (1996) Very long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders. Lipids 31(Suppl):S141-144. https://doi.org/10.1007/BF02637066
doi: 10.1007/BF02637066
pubmed: 8729109
Mundwiler A, Shakkottai VG (2018) Autosomal-dominant cerebellar ataxias. Handb Clin Neurol 147:173–185. https://doi.org/10.1016/B978-0-444-63233-3.00012-9
doi: 10.1016/B978-0-444-63233-3.00012-9
pubmed: 29325610
Nagaraja RY, Sherry DM, Fessler JL, Stiles MA, Li F, Multani K et al (2021) W246G mutant ELOVL4 impairs synaptic plasticity in parallel and climbing fibers and causes motor defects in a rat model of SCA34. Mol Neurobiol 58:4921–4943. https://doi.org/10.1007/s12035-021-02439-1
doi: 10.1007/s12035-021-02439-1
pubmed: 34227061
pmcid: 8497303
Oldfors A, Sourander P (1981) Storage of lipofuscin in neurons in mucopolysaccharidosis. Report on a case of Sanfilippo’s syndrome with histochemical and electron-microscopic findings. Acta Neuropathol 54:287–292. https://doi.org/10.1007/BF00697002
doi: 10.1007/BF00697002
pubmed: 6267869
Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T et al (2015) A novel mutation in ELOVL4 leading to spinocerebellar ataxia (SCA) with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. JAMA Neurol 72:797–805. https://doi.org/10.1001/jamaneurol.2015.0610
doi: 10.1001/jamaneurol.2015.0610
pubmed: 26010696
Ozaki K, Irioka T, Uchihara T, Yamada A, Nakamura A, Majima T et al (2021) Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study. Acta Neuropathol Commun 9:172. https://doi.org/10.1186/s40478-021-01272-w
doi: 10.1186/s40478-021-01272-w
pubmed: 34689836
pmcid: 8543940
Powers JM, Kenjarski TP, Moser AB, Moser HW (1999) Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells. Acta Neuropathol 98:129–134. https://doi.org/10.1007/s004010051060
doi: 10.1007/s004010051060
pubmed: 10442551
Presentey B, Jerushalmy Z (1979) Specificity of various methods used to identify phospholipids in tissues. Acta Histochem Cytochem 12:330–336. https://doi.org/10.1267/ahc.12.330
doi: 10.1267/ahc.12.330
Roels F, Cornelis A, Poll-The BT, Aubourg P, Ogier H, Scotto J et al (1986) Hepatic peroxisomes are deficient in infantile refsum disease: a cytochemical study of 4 cases. Am J Med Genet 25:257–271. https://doi.org/10.1002/ajmg.1320250210
doi: 10.1002/ajmg.1320250210
pubmed: 2430454
Seidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124:1–21. https://doi.org/10.1007/s00401-012-1000-x
doi: 10.1007/s00401-012-1000-x
pubmed: 22684686
Sherry DM, Hopiavuori BR, Stiles MA, Rahman NS, Ozan KG, Deak F et al (2017) Distribution of ELOVL4 in the developing and adult mouse brain. Front Neuroanat 11:38. https://doi.org/10.3389/fnana.2017.00038
doi: 10.3389/fnana.2017.00038
pubmed: 28507511
pmcid: 5410580
Theda C, Moser AB, Powers JM, Moser HW (1992) Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination. J Neurol Sci 110:195–204. https://doi.org/10.1016/0022-510x(92)90028-j
doi: 10.1016/0022-510x(92)90028-j
pubmed: 1506859
Torvik A, Torp S, Kase BF, Ek J, Skjeldal O, Stokke O (1988) Infantile Refsum’s disease: a generalized peroxisomal disorder. Case report with postmortem examination. J Neurol Sci 85:39–53. https://doi.org/10.1016/0022-510x(88)90034-2
doi: 10.1016/0022-510x(88)90034-2
pubmed: 2455020
Ulrich J, Herschkowitz N, Heitz P, Sigrist T, Baerlocher P (1978) Adrenoleukodystrophy. Preliminary report of a connatal case. Light- and electron microscopical, immunohistochemical and biochemical findings. Acta Neuropathol 43:77–83. https://doi.org/10.1007/BF00685001
doi: 10.1007/BF00685001
pubmed: 209659
Walkley SU, Suzuki K, Suzuki K (2015) Lysosomal Diseases. In: Love S, Budka H, Ironside JW, Perry A (eds) Greenfield’s neuropathology. CRC Press, Boca Raton, FL, pp 439–522