Abstract
At the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3–9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.
About the author
Alessio Guglielmi studied at Università degli Studi di Udine and obtained his bachelor’s degree in biotechnology based on a thesis project about implementations on ePCR in complex bacteriological populations. He then obtained his Master’s degree in medical biotechnology from the same university based on a thesis project about searching for new disease-associated isoforms of α-synuclein protein extracted from olfactory neurons of living patients and postmortem brains. He obtained his Ph.D. at the International Centre of Genetic Engineering and Biotechnology, working on a project aimed to find new insights on REEP1 antistress functions in AD.
References
Allison, R., Edgar, J.R., Pearson, G., Rizo, T., Newton, T., Günther, S., Berner, F., Hague, J., Connell, J.W., Winkler, J., et al. (2017). Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. J. Cell Biol. 216, 1337–1355.10.1083/jcb.201609033Search in Google Scholar PubMed PubMed Central
Appocher, C., Klima, R., and Feiguin, F. (2014). Functional screening in Drosophila reveals the conserved role of REEP1 in promoting stress resistance and preventing the formation of τ aggregates. Hum. Mol. Genet. 23, 6762–6772.10.1093/hmg/ddu393Search in Google Scholar PubMed
Beetz, C., Schüle, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B.P.H., Frints, S.G.M., van Zelst-Stams, W.A.G., Byrne, P., Otto, S., et al. (2008). REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain J. Neurol. 131, 1078–1086.10.1093/brain/awn026Search in Google Scholar PubMed PubMed Central
Beetz, C., Pieber, T.R., Hertel, N., Schabhüttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., et al. (2012). Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am. J. Hum. Genet. 91, 139–145.10.1016/j.ajhg.2012.05.007Search in Google Scholar PubMed PubMed Central
Beetz, C., Koch, N., Khundadze, M., Zimmer, G., Nietzsche, S.,Hertel, N., Huebner, A.-K., Mumtaz, R., Schweizer, M., Dirren, E., et al. (2013). A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. J. Clin. Invest. 123, 4273–4282.10.1172/JCI65665Search in Google Scholar PubMed PubMed Central
Behan, W.M. and Maia, M. (1974). Strümpell’s familial spastic paraplegia: genetics and neuropathology. J. Neurol. Neurosurg. Psychiatry 37, 8–20.10.1136/jnnp.37.1.8Search in Google Scholar PubMed PubMed Central
Behrens, M., Bartelt, J., Reichling, C., Winnig, M., Kuhn, C., and Meyerhof, W. (2006). Members of RTP and REEP gene families influence functional bitter taste receptor expression. J. Biol. Chem. 281, 20650–20659.10.1074/jbc.M513637200Search in Google Scholar PubMed
Béreau, M., Anheim, M., Chanson, J.-B., Tio, G., Echaniz-Laguna, A., Depienne, C., Collongues, N., and de Sèze, J. (2015). Dalfampridine in hereditary spastic paraplegia: a prospective, open study. J. Neurol. 262, 1285–1288.10.1007/s00415-015-7707-6Search in Google Scholar PubMed
Bertolucci, F., Di Martino, S., Orsucci, D., Ienco, E.C., Siciliano, G., Rossi, B., Mancuso, M., and Chisari, C. (2015). Robotic gait training improves motor skills and quality of life in hereditary spastic paraplegia. Neurorehabilitation 36, 93–99.10.3233/NRE-141196Search in Google Scholar PubMed
Björk, S., Hurt, C.M., Ho, V.K., and Angelotti, T. (2013). REEPs are membrane shaping adapter proteins that modulate specific G protein-coupled receptor trafficking by affecting ER cargo capacity. PLoS One 8, e76366.10.1371/journal.pone.0076366Search in Google Scholar PubMed PubMed Central
Charvin, D., Cifuentes-Diaz, C., Fonknechten, N., Joshi, V., Hazan, J., Melki, J., and Betuing, S. (2003). Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Hum. Mol. Genet. 12, 71–78.10.1093/hmg/ddg004Search in Google Scholar PubMed
Eastman, S.W., Yassaee, M., and Bieniasz, P.D. (2009). A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J. Cell Biol. 184, 881–894.10.1083/jcb.200808041Search in Google Scholar PubMed PubMed Central
Edwards, T.L., Clowes, V.E., Tsang, H.T.H., Connell, J.W., Sanderson, C.M., Luzio, J.P., and Reid, E. (2009). Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5. Biochem. J. 423, 31–39.10.1042/BJ20082398Search in Google Scholar PubMed PubMed Central
Errico, A., Ballabio, A., and Rugarli, E.I. (2002). Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum. Mol. Genet. 11, 153–163.10.1093/hmg/11.2.153Search in Google Scholar PubMed
Falk, J., Rohde, M., Bekhite, M.M., Neugebauer, S., Hemmerich, P., Kiehntopf, M., Deufel, T., Hübner, C.A., and Beetz, C. (2014). Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Hum. Mutat. 35, 497–504.10.1002/humu.22521Search in Google Scholar PubMed
Fink, J.K. (2003). Advances in the hereditary spastic paraplegias. Exp. Neurol. 184, S106–S110.10.1016/j.expneurol.2003.08.005Search in Google Scholar PubMed
Fink, J.K. (2013). Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. (Berl.) 126, 307–328.10.1007/s00401-013-1115-8Search in Google Scholar PubMed PubMed Central
Finsterer, J., Löscher, W., Quasthoff, S., Wanschitz, J., Auer-Grumbach, M., and Stevanin, G. (2012). Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J. Neurol. Sci. 318, 1–18.10.1016/j.jns.2012.03.025Search in Google Scholar PubMed
Fontaine, B., Davoine, C.S., Dürr, A., Paternotte, C., Feki, I., Weissenbach, J., Hazan, J., and Brice, A. (2000). A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am. J. Hum. Genet. 66, 702–707.10.1086/302776Search in Google Scholar PubMed PubMed Central
Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Solé, G., Coupry, I., Pilliod, J., Martin-Négrier, M.-L., Fedirko, E., et al. (2011). REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Hum. Mutat. 32, 1118–1127.10.1002/humu.21542Search in Google Scholar PubMed
Harding, A.E. (1993). Hereditary spastic paraplegias. Semin. Neurol. 13, 333–336.10.1055/s-2008-1041143Search in Google Scholar PubMed
Hashimoto, Y., Shirane, M., Matsuzaki, F., Saita, S., Ohnishi, T., and Nakayama, K.I. (2014). Protrudin regulates endoplasmic reticulum morphology and function associated with the pathogenesis of hereditary spastic paraplegia. J. Biol. Chem. 289, 12946–12961.10.1074/jbc.M113.528687Search in Google Scholar PubMed PubMed Central
Hewamadduma, C., McDermott, C., Kirby, J., Grierson, A., Panayi, M., Dalton, A., Rajabally, Y., and Shaw, P. (2009). New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics 10, 105–110.10.1007/s10048-008-0163-zSearch in Google Scholar PubMed
Hooper, C., Puttamadappa, S.S., Loring, Z., Shekhtman, A., and Bakowska, J.C. (2010). Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets. BMC Biol. 8, 72.10.1186/1741-7007-8-72Search in Google Scholar PubMed PubMed Central
Hurt, C.M., Björk, S., Ho, V.K., Gilsbach, R., Hein, L., and Angelotti, T. (2014). REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues. Brain Res. 1545, 12–22.10.1016/j.brainres.2013.12.008Search in Google Scholar PubMed PubMed Central
Jia, X., Madireddy, L., Caillier, S., Santaniello, A., Esposito, F., Comi, G., Stuve, O., Zhou, Y., Taylor, B., Kilpatrick, T., et al. (2018). Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. Ann. Neurol. 84, 51–63.10.1002/ana.25263Search in Google Scholar PubMed PubMed Central
Kenwrick, S., Watkins, A., and De Angelis, E. (2000). Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Hum. Mol. Genet. 9, 879–886.10.1093/hmg/9.6.879Search in Google Scholar PubMed
Lavie, J., Serrat, R., Bellance, N., Courtand, G., Dupuy, J.-W., Tesson, C., Coupry, I., Brice, A., Lacombe, D., Durr, A., et al. (2017). Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Hum. Mol. Genet. 26, 674–685.10.1093/hmg/ddw425Search in Google Scholar PubMed
Lim, Y., Cho, I.-T., Schoel, L.J., Cho, G., and Golden, J.A. (2015). Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts. Ann. Neurol. 78, 679–696.10.1002/ana.24488Search in Google Scholar PubMed PubMed Central
Liu, S.G., Che, F.Y., Heng, X.Y., Li, F.F., Huang, S.Z., Lu, D.G., Hou, S.J., Liu, S.E., Wang, Q., Wang, H.P., et al. (2009). Clinical and genetic study of a novel mutation in the REEP1 gene. Synapse 63, 201–205.10.1002/syn.20602Search in Google Scholar PubMed
McCorquodale, D.S., Ozomaro, U., Huang, J., Montenegro, G., Kushman, A., Citrigno, L., Price, J., Speziani, F., Pericak-Vance, M.A., and Züchner, S. (2011). Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. Clin. Genet. 79, 523–530.10.1111/j.1399-0004.2010.01501.xSearch in Google Scholar PubMed PubMed Central
McDermott, C., White, K., Bushby, K., and Shaw, P. (2000). Hereditary spastic paraparesis: a review of new developments. J. Neurol. Neurosurg. Psychiatry 69, 150–160.10.1136/jnnp.69.2.150Search in Google Scholar PubMed PubMed Central
McMonagle, P., Webb, S., and Hutchinson, M. (2002). The prevalence of “pure” autosomal dominant hereditary spastic paraparesis in the island of Ireland. J. Neurol. Neurosurg. Psychiatry 72, 43–46.10.1136/jnnp.72.1.43Search in Google Scholar PubMed PubMed Central
Miura, S., Shibata, H., Kida, H., Noda, K., Tomiyasu, K., Yamamoto, K., Iwaki, A., Ayabe, M., Aizawa, H., Taniwaki, T., et al. (2008). Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. J. Neurol. Sci. 273, 88–92.10.1016/j.jns.2008.06.027Search in Google Scholar PubMed
Mondrup, K. and Pedersen, E. (1984). The clinical effect of the GABA-agonist, progabide, on spasticity. Acta Neurol. Scand. 69, 200–206.10.1111/j.1600-0404.1984.tb07802.xSearch in Google Scholar PubMed
Park, S.H., Zhu, P.-P., Parker, R.L., and Blackstone, C. (2010). Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J. Clin. Invest. 120, 1097–1110.10.1172/JCI40979Search in Google Scholar PubMed PubMed Central
Pease, W.S. (1998). Therapeutic electrical stimulation for spasticity: quantitative gait analysis. Am. J. Phys. Med. Rehabil. 77, 351–355.10.1097/00002060-199807000-00021Search in Google Scholar PubMed
Reid, E., Kloos, M., Ashley-Koch, A., Hughes, L., Bevan, S., Svenson, I.K., Graham, F.L., Gaskell, P.C., Dearlove, A., Pericak-Vance, M.A., et al. (2002). A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, 1189–1194.10.1086/344210Search in Google Scholar PubMed PubMed Central
Renvoisé, B., Malone, B., Falgairolle, M., Munasinghe, J., Stadler, J., Sibilla, C., Park, S.H., and Blackstone, C. (2016). Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation. Hum. Mol. Genet. 25, 5111–5125.Search in Google Scholar
Richard, S., Lavie, J., Banneau, G., Voirand, N., Lavandier, K., and Debouverie, M. (2017). Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: case report and literature review. Medicine (Baltimore) 96, e5911.10.1097/MD.0000000000005911Search in Google Scholar PubMed PubMed Central
Saito, H., Kubota, M., Roberts, R.W., Chi, Q., and Matsunami, H. (2004). RTP family members induce functional expression of mammalian odorant receptors. Cell 119, 679–691.10.1016/j.cell.2004.11.021Search in Google Scholar PubMed
Schlang, K.J., Arning, L., Epplen, J.T., and Stemmler, S. (2008). Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC Med. Genet. 9, 71.10.1186/1471-2350-9-71Search in Google Scholar
Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., and Schuelke, M. (2015). Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy. Neurol. Genet. 1, e32.10.1212/NXG.0000000000000032Search in Google Scholar
Schwarz, G.A. and Liu, C.N. (1956). Hereditary (familial) spastic paraplegia; further clinical and pathologic observations. AMA Arch. Neurol. Psychiatry 75, 144–162.10.1001/archneurpsyc.1956.02330200038005Search in Google Scholar
Sedel, F., Fontaine, B., Saudubray, J.M., and Lyon-Caen, O. (2007). Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach. J. Inherit. Metab. Dis. 30, 855–864.10.1007/s10545-007-0745-1Search in Google Scholar
Sills, G.J. (2006). The mechanisms of action of gabapentin and pregabalin. Curr. Opin. Pharmacol. 6, 108–113.10.1016/j.coph.2005.11.003Search in Google Scholar
Silva, M.C., Coutinho, P., Pinheiro, C.D., Neves, J.M., and Serrano, P. (1997). Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J. Clin. Epidemiol. 50, 1377–1384.10.1016/S0895-4356(97)00202-3Search in Google Scholar
de Souza, P.V.S., de Rezende Pinto, W.B.V., de Rezende Batistella, G.N., Bortholin, T., and Oliveira, A.S.B. (2016). Hereditary spastic paraplegia: clinical and genetic hallmarks. Cerebellum (Lond.).10.1007/s12311-016-0803-zSearch in Google Scholar PubMed
Stevens, S.J.C., Blom, E.W., Siegelaer, I.T.J., and Smeets, E.E.J.G.L. (2015). A recurrent deletion syndrome at chromosome bands 2p11.2-2p12 flanked by segmental duplications at the breakpoints and including REEP1. Eur. J. Hum. Genet. 23, 543–546.10.1038/ejhg.2014.124Search in Google Scholar PubMed PubMed Central
Tsaousidou, M.K., Ouahchi, K., Warner, T.T., Yang, Y., Simpson, M.A., Laing, N.G., Wilkinson, P.A., Madrid, R.E., Patel, H., Hentati, F., et al. (2008). Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82, 510–515.10.1016/j.ajhg.2007.10.001Search in Google Scholar PubMed PubMed Central
Tzschach, A., Graul-Neumann, L.M., Konrat, K., Richter, R., Ebert, G., Ullmann, R., and Neitzel, H. (2009). Interstitial deletion 2p11.2-p12: report of a patient with mental retardation and review of the literature. Am. J. Med. Genet. A. 149A, 242–245.10.1002/ajmg.a.32637Search in Google Scholar PubMed
Ulengin, I., Park, J.J., and Lee, T.H. (2015). ER network formation and membrane fusion by atlastin1/SPG3A disease variants. Mol. Biol. Cell 26, 1616–1628.10.1091/mbc.E14-10-1447Search in Google Scholar PubMed PubMed Central
Vanderver, A., Tonduti, D., Auerbach, S., Schmidt, J.L., Parikh, S., Gowans, G.C., Jackson, K.E., Brock, P.L., Patterson, M., Nehrebecky, M., et al. (2012). Neurotransmitter abnormalities and response to supplementation in SPG11. Mol. Genet. Metab. 107, 229–233.10.1016/j.ymgme.2012.05.020Search in Google Scholar PubMed PubMed Central
Wijemanne, S. and Jankovic, J. (2015). Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat. Rev. Neurol. 11, 414–424.10.1038/nrneurol.2015.86Search in Google Scholar PubMed
Yalçın, B., Zhao, L., Stofanko, M., O’Sullivan, N.C., Kang, Z.H., Roost, A., Thomas, M.R., Zaessinger, S., Blard, O., Patto, A.L., et al. (2017). Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins. eLife 6, pii: e23882.10.7554/eLife.23882Search in Google Scholar PubMed PubMed Central
Zhang, Y., Roxburgh, R., Huang, L., Parsons, J., and Davies, T.C. (2014). The effect of hydrotherapy treatment on gait characteristics of hereditary spastic paraparesis patients. Gait Posture 39, 1074–1079.10.1016/j.gaitpost.2014.01.010Search in Google Scholar PubMed
Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C.H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., et al. (2001). Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat. Genet. 29, 326–331.10.1038/ng758Search in Google Scholar PubMed
Zhao, C., Lou, Y., Wang, Y., Wang, D., Tang, L., Gao, X., Zhang, K., Xu, W., Liu, T., and Xiao, J. (2019). A gene expression signature-based nomogram model in prediction of breast cancer bone metastases. Cancer Med. 8, 200–208.10.1002/cam4.1932Search in Google Scholar PubMed PubMed Central
Zheng, P., Chen, Q., Tian, X., Qian, N., Chai, P., Liu, B., Hu, J., Blackstone, C., Zhu, D., Teng, J., et al. (2018). DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling. Cell Res. 28, 833–854.10.1038/s41422-018-0065-zSearch in Google Scholar PubMed PubMed Central
Züchner, S., Kail, M.E., Nance, M.A., Gaskell, P.C., Svenson, I.K., Marchuk, D.A., Pericak-Vance, M.A., and Ashley-Koch, A.E. (2006a). A new locus for dominant hereditary spastic paraplegia maps to chromosome 2p12. Neurogenetics 7, 127–129.10.1007/s10048-006-0029-1Search in Google Scholar PubMed
Züchner, S., Kail, M.E., Nance, M.A., Gaskell, P.C., Svenson, I.K., Marchuk, D.A., Pericak-Vance, M.A., and Ashley-Koch, A.E. (2006b). A new locus for dominant hereditary spastic paraplegia maps to chromosome 2p12. Neurogenetics 7, 127–129.10.1007/s10048-006-0029-1Search in Google Scholar
Züchner, S., Wang, G., Tran-Viet, K.-N., Nance, M.A., Gaskell, P.C., Vance, J.M., Ashley-Koch, A.E., and Pericak-Vance, M.A. (2006c). Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am. J. Hum. Genet. 79, 365–369.10.1086/505361Search in Google Scholar PubMed PubMed Central
©2020 Walter de Gruyter GmbH, Berlin/Boston