, Volume 10, Issue 3, pp 217–228 | Cite as

Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1

  • Michael C. HannaEmail author
  • Craig BlackstoneEmail author
Original Article


Mast syndrome (SPG21) is an autosomal-recessive complicated form of hereditary spastic paraplegia characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product acidic cluster protein 33 (ACP33)/maspardin underlies this disorder, likely causing loss of protein function. However, little is known about the function of maspardin. Here, we report that maspardin localizes prominently to cytoplasm as well as to membranes, possibly at trans-Golgi network/late endosomal compartments. Immunoprecipitation of maspardin with identification of coprecipitating proteins by mass spectrometry revealed the aldehyde dehydrogenase ALDH16A1 as an interacting protein. This interaction was confirmed using overexpressed proteins as well as by fusion protein pull down experiments, and these proteins colocalized in cells. Further studies of the function of ALDH16A1 and the role of the maspardin–ALDH16A1 interaction in neuronal cells may clarify the cellular pathogenesis of Mast syndrome.


Aldehyde dehydrogenase ACP33 CD4 Spastic paraplegia Endocytosis 



The authors wish to thank Dr. Howard Jaffe (NINDS Protein/Peptide Sequencing Facility) for mass spectrometry, James Nagle and Debbie Kauffman (NINDS DNA Sequencing Facility) for DNA sequencing, and Henri Jupille and Julia Stadler for technical assistance. This study was supported by the Intramural Research Program of the NIH, National Institutes of Neurological Disorders and Stroke.


  1. 1.
    Schwarz GA, Liu CN (1956) Hereditary (familial) spastic paraplegia: further clinical and pathologic observations. AMA Arch Neurol Psychiatry 75:144–162PubMedGoogle Scholar
  2. 2.
    Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1:1151–1155. doi: 10.1016/S0140-6736(83)92879-9 PubMedCrossRefGoogle Scholar
  3. 3.
    Crosby AH, Proukakis C (2002) Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet 71:1009–1016. doi: 10.1086/344206 PubMedCrossRefGoogle Scholar
  4. 4.
    Reid E (2003) Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet 40:81–86. doi: 10.1136/jmg.40.2.81 PubMedCrossRefGoogle Scholar
  5. 5.
    Fink JK (2006) Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 6:65–76. doi: 10.1007/s11910-996-0011-1 PubMedCrossRefGoogle Scholar
  6. 6.
    Soderblom C, Blackstone C (2006) Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther 109:42–56. doi: 10.1016/j.pharmthera.2005.06.001 PubMedCrossRefGoogle Scholar
  7. 7.
    Züchner S (2007) The genetics of hereditary spastic paraplegia and implications for drug therapy. Expert Opin Pharmacother 8:1433–1439. doi: 10.1517/14656566.8.10.1433 PubMedCrossRefGoogle Scholar
  8. 8.
    Stevanin G, Ruberg M, Brice A (2008) Recent advances in the genetics of spastic paraplegias. Curr Neurol Neurosci Rep 8:198–210. doi: 10.1007/s11910-008-0032-z PubMedCrossRefGoogle Scholar
  9. 9.
    Simpson MA, Cross H, Proukakis C, Pryde A, Hershberger R, Chatonnet A, Patton MA, Crosby AH (2003) Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 73:1147–1156. doi: 10.1086/379522 PubMedCrossRefGoogle Scholar
  10. 10.
    Zeitlmann L, Sirim P, Kremmer E, Kolanus W (2001) Cloning of ACP33 as a novel intracellular ligand of CD4. J Biol Chem 276:9123–9132. doi: 10.1074/jbc.M009270200 PubMedCrossRefGoogle Scholar
  11. 11.
    Zhu P-P, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, Blackstone C (2003) Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem 278:49063–49071. doi: 10.1074/jbc.M306702200 PubMedCrossRefGoogle Scholar
  12. 12.
    Zhu P-P, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C (2004) Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem 279:35967–35974. doi: 10.1074/jbc.M404105200 PubMedCrossRefGoogle Scholar
  13. 13.
    Blackstone C, Roberts RG, Seeburg DP, Sheng M (2003) Interaction of the deafness–dystonia protein DDP/TIMM8a with the signal transduction adaptor molecule STAM1. Biochem Biophys Res Commun 305:345–352. doi: 10.1016/S0006-291X(03)00767-8 PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng YL, Li BS, Veeranna, Pant HC (2003) Phosphorylation of the head domain of neurofilament protein (NF-M): a factor regulating topographic phosphorylation of NF-M tail domain KSP sites in neurons. J Biol Chem 278:24026–24032. doi: 10.1074/jbc.M303079200 PubMedCrossRefGoogle Scholar
  15. 15.
    Schrag JD, Li YG, Wu S, Cygler M (1991) Ser-His-Glu triad forms the catalytic site of the lipase from Geotrichum candidum. Nature 351:761–764. doi: 10.1038/351761a0 PubMedCrossRefGoogle Scholar
  16. 16.
    Holmquist M (2000) Alpha beta-hydrolase fold enzymes: structures, functions and mechanisms. Curr Protein Pept Sci 1:209–235. doi: 10.2174/1389203003381405 PubMedCrossRefGoogle Scholar
  17. 17.
    Elmi F, Lee HT, Huang JY, Hsieh YC, Wang YL, Chen YJ, Shaw SY, Chen CJ (2005) Stereoselective esterase from Pseudomonas putida IFO12996 reveals alpha/beta hydrolase folds for d-beta-acetylthioisobutyric acid synthesis. J Bacteriol 187:8470–8476. doi: 10.1128/JB.187.24.8470-8476.2005 PubMedCrossRefGoogle Scholar
  18. 18.
    Hecht HJ, Sobek H, Haag T, Pfeifer O, van Pee KH (1994) The metal-ion-free oxidoreductase from Streptomyces aureofaciens has an alpha/beta hydrolase fold. Nat Struct Biol 1:532–537. doi: 10.1038/nsb0894-532 PubMedCrossRefGoogle Scholar
  19. 19.
    Chen CC, Han Y, Niu W, Kulakova AN, Howard A, Quinn JP, Dunaway-Mariano D, Herzberg O (2006) Structure and kinetics of phosphonopyruvate hydrolase from Variovorax sp. Pal2: new insight into the divergence of catalysis within the PEP mutase/isocitrate lyase superfamily. Biochemistry 45:11491–11504. doi: 10.1021/bi061208l PubMedCrossRefGoogle Scholar
  20. 20.
    Marchitti SA, Brocker C, Stagos D, Vasiliou (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4:697–720. doi: 10.1517/17425255.4.6.697 PubMedCrossRefGoogle Scholar
  21. 21.
    Jacobs FMJ, Smits SM, Noorlander CW, von Oerthel L, van der Linden AJ, Burbach JP, Smidt MP (2007) Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development 134:2673–2684. doi: 10.1242/dev.02865 PubMedCrossRefGoogle Scholar
  22. 22.
    Lassen N, Bateman JB, Estey T, Kuszak JR, Nees DW, Piatigorsky J, Duester G, Day BJ, Huang J, Hines LM, Vasiliou V (2007) Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1(−/−)/Aldh1a1(−/−) knock-out mice. J Biol Chem 282:25668–25676. doi: 10.1074/jbc.M702076200 PubMedCrossRefGoogle Scholar
  23. 23.
    Vasiliou V, Nebert DW (2005) Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2:138–143PubMedGoogle Scholar
  24. 24.
    Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176. doi: 10.1038/nature05453 PubMedCrossRefGoogle Scholar
  25. 25.
    Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (1998) PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 94:205–216. doi: 10.1016/S0092-8674(00)81420-8 PubMedCrossRefGoogle Scholar
  26. 26.
    Rizzo WB (2007) Sjögren–Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab 90:1–9. doi: 10.1016/j.ymgme.2006.08.006 PubMedCrossRefGoogle Scholar
  27. 27.
    Rizzo WB, Carney G (2005) Sjögren–Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mutat 26:1–10. doi: 10.1002/humu.20181 PubMedCrossRefGoogle Scholar
  28. 28.
    Valle D, Goodman SI, Applegarth DA, Shih VE, Phang JM (1976) Type II hyperprolinemia: 1-pyrroline-5-carboxylic acid dehydrogenase deficiency in cultured skin fibroblasts and circulating lymphocytes. J Clin Invest 58:598–603. doi: 10.1172/JCI108506 PubMedCrossRefGoogle Scholar
  29. 29.
    Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jakobs C (1998) 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 29:14–22. doi: 10.1055/s-2007-973527 PubMedCrossRefGoogle Scholar
  30. 30.
    Vasiliou V, Pappa A (2000) Polymorphisms of human aldehyde dehydrogenases: consequences for drug metabolism and disease. Pharmacology 61:192–198. doi: 10.1159/000028400 PubMedCrossRefGoogle Scholar
  31. 31.
    Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MAAP, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT (2006) Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 12:307–309. doi: 10.1038/nm1366 PubMedCrossRefGoogle Scholar
  32. 32.
    Deak KL, Dickerson ME, Linney E, Enterline DS, George TM, Melvin EC, Graham FL, Siegel DG, Hammock P, Mehltretter L, Bassuk AG, Kessler JA, Gilbert JR, Speer MC, NTD Collaborative Group (2005) Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res A Clin Mol Teratol 73:868–875. doi: 10.1002/bdra.20183 PubMedCrossRefGoogle Scholar
  33. 33.
    Kamino K, Nagasaka K, Imagawa M, Yamamoto H, Yoneda H, Ueki A, Kitamura S, Namekata K, Miki T, Ohta S (2000) Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population. Biochem Biophys Res Commun 273:192–196. doi: 10.1006/bbrc.2000.2923 PubMedCrossRefGoogle Scholar
  34. 34.
    Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH (2008) Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet 82:510–515. doi: 10.1016/j.ajhg.2007.10.001 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Biological and Environmental SciencesTexas A & M University-CommerceCommerceUSA
  2. 2.Cellular Neurology Unit, Neurogenetics Branch, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA

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