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Update on the Genetics of Spastic Paraplegias

  • Maxime Boutry
  • Sara Morais
  • Giovanni StevaninEmail author
Genetics (V. Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics

Abstract

Purpose of Review

Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in complex forms by additional neurological signs. We review here the major steps toward understanding the molecular basis of these diseases made over the last 10 years.

Recent Findings

Our perception of the intricate connections between clinical, genetic, and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which > 60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations, and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects. Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function and based on studies on patient samples and animal models. These mechanisms include mainly abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination, and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected.

Summary

Recent major advances in our understanding of these diseases have revealed unifying pathogenic models that could be targeted in the much-needed development of new treatments.

Keywords

Hereditary spastic paraplegia Motor neuron Pyramidal syndrome Neurodegenerative diseases Intracellular trafficking Neurological diseases 

Notes

Acknowledgments

We thank Drs F Mochel, F Darios, KH El-Hachimi, and V Anquetil for fruitful discussions.

Funding Information

The authors’ work is funded by the European Union H2020 program (SOLVE-RD, to GS), the Spastic Paraplegia Foundation [US] (to GS), the Association Strümpell-Lorrain [FR] (to GS), the Agence Nationale de la Recherche [FR] (Spatax-Quest, to GS), and the E-Rare Program (Prepare, to GS). MB and SM held PhD fellowships from the ED3C Doctoral School (France) and the Fundação para a Ciência e a Tecnologia (Portugal), respectively.

Compliance with Ethical Standards

Conflict of Interest

Giovanni Stevanin reports grants from the European Union H2020 programme, grants from Spastic Paraplegia Foundation, grants from Association Strumpell Lorrain, grants from Agence Nationale de la Recherche, and grants from Erare Program, during the conduct of the study. In addition, Dr. Stevanin has been issued a patent on Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases. Maxime Boutry reports personal fees from French Ministry of Research (Doctoral School ED3C), during the conduct of the study. In addition, Dr. Boutry has been issued a patent on Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases. Sara Morais reports personal fees from FCT (Fundação para a Ciência e Tecnologia), Portugal, during the conduct of the study.

Human and Animal Rights and Informed Consent

This article is a review and reports only studies approved by editorial boards based on peer reviews. When we cited our own work, all the procedures performed in the studies involving human materials or animals were conducted in accordance with the ethical standards of our institution, with informed consent obtained from patients and approval from ethics committees.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1:1151–5.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307–28.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Deluca GC, Ebers GC, Esiri MM. The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol. 2004;30:576–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Schwarz GA, Liu CN. Hereditary (familial) spastic paraplegia; further clinical and pathologic observations. AMA Arch Neurol Psychiatry. 1956;75:144–62.PubMedCrossRefGoogle Scholar
  5. 5.
    Blackstone C, Kane CJO, Reid E, O’Kane CJ, Reid E. Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci. 2011;12:31–42.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Denora PS, Smets K, Zolfanelli F, Ceuterick-de Groote C, Casali C, Deconinck T, et al. Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions. Brain. 2016;139(Pt 6):1723–34.PubMedPubMedCentralGoogle Scholar
  8. 8.
    França MC, D’Abreu A, Maurer-Morelli CV, Seccolin R, Appenzeller S, Alessio A, et al. Prospective neuroimaging study in hereditary spastic paraplegia with thin corpus callosum. Mov Disord. 2007;22:1556–62.PubMedCrossRefGoogle Scholar
  9. 9.
    • Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83 This meta-analysis study reanalyzed 22 reports on > 14,500 patients from 16 countries, to estimate the global prevalence of hereditary ataxias and spastic paraplegias. PubMedCrossRefGoogle Scholar
  10. 10.
    Tesson C, Koht J, Stevanin G. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet. 2015;134:511–38.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hensiek A, Kirker S, Reid E. Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing. J Neurol. 2015;262:1601–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Parodi L, Fenu S, Stevanin G, Durr A. Hereditary spastic paraplegia: more than an upper motor neuron disease. Rev Neurol (Paris). 2017;173:352–60.CrossRefGoogle Scholar
  13. 13.
    Parodi L, Coarelli G, Stevanin G, Brice A, Durr A. Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018;31(4):462–71.PubMedGoogle Scholar
  14. 14.
    •• Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343(6170):506–11 The authors analyzed a cohort of 55 consanguineous families with HSP by exome sequencing, with gene validation in zebrafish experiments in a few cases. They identified the cause of the disease in three quarters of the families as a defect of a known or new ( n = 18) HSP gene. Bioinformatic analyses identified 589 interconnected genes, all candidates for HSP, some of which are overrepresented among the causal genes for neurodegenerative diseases. PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Burguez D, Polese-Bonatto M, Scudeiro LAJ, Björkhem I, Schöls L, Jardim LB, et al. Clinical and molecular characterization of hereditary spastic paraplegias: a next-generation sequencing panel approach. J Neurol Sci. 2017;383:18–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Dong EL, Wang C, Wu S, Lu YQ, Lin XH, Su HZ, et al. Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. Mol Neurodegener. 2018;13(1):36.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Chrestian N, Dupré N, Gan-Or Z, Szuto A, Chen S, Venkitachalam A, et al. Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet. 2016;3(1):e122.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Schüle R, Wiethoff S, Martus P, Karle KN, Otto S, Klebe S, et al. Hereditary spastic paraplegia: clinicogenetic lessons from 608 patients. Ann Neurol. 2016;79(4):646–58.PubMedCrossRefGoogle Scholar
  19. 19.
    Ribaï P, Depienne C, Fedirko E, Jothy AC, Viveweger C, Hahn-Barma V, et al. Mental deficiency in three families with SPG4 spastic paraplegia. Eur J Hum Genet. 2008;16(1):97–104.PubMedCrossRefGoogle Scholar
  20. 20.
    Chamard L, Ferreira S, Pijoff A, Silvestre M, Berger E, Magnin E. Cognitive impairment involving social cognition in SPG4 hereditary spastic paraplegia. Behav Neurol. 2016;2016:6423461.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Stevanin G, Azzedine H, Denora P, Boukhris A, Tazir M, Lossos A, et al. SPATAX consortium. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain. 2008;131:772–84.PubMedCrossRefGoogle Scholar
  22. 22.
    Gan-Or Z, Bouslam N, Birouk N, Lissouba A, Chambers DB, Vérièpe J, et al. Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia. Am J Hum Genet. 2016;98:1038–46.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wang Y, Hersheson J, Lopez D, Hammer M, Liu Y, Lee KH, et al. Defects in the CAPN1 gene result in alterations in cerebellar development and cerebellar ataxia in mice and humans. Cell Rep. 2016;16(1):79–91.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tadic V, Klein C, Hinrichs F, Münchau A, Lohmann K, Brüggemann N. CAPN1 mutations are associated with a syndrome of combined spasticity and ataxia. J Neurol. 2017;264(5):1008–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Travaglini L, Bellacchio E, Aiello C, Pro S, Bertini E, Nicita F. Expanding the clinical phenotype of CAPN1-associated mutations: a new case with congenital-onset pure spastic paraplegia. J Neurol Sci. 2017;378:210–2.PubMedCrossRefGoogle Scholar
  26. 26.
    Kocoglu C, Gundogdu A, Kocaman G, Kahraman-Koytak P, Uluc K, Kiziltan G, et al. Homozygous CAPN1 mutations causing a spastic-ataxia phenotype in 2 families. Neurol Genet. 2018;4(1):e218.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Verny C, Guegen N, Desquiret V, Chevrollier A, Prundean A, Dubas F, et al. Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion. 2011;11:70–5.PubMedCrossRefGoogle Scholar
  28. 28.
    • Esteves T, Durr A, Mundwiller E, Loureiro JL, Boutry M, Gonzalez MA, et al. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am J Hum Genet. 2014;94:268–77 This study illustrates how dominant and recessive inheritance can be explained by the effects and nature of mutations of the same HSP-related gene. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015;138:2191–205.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, et al. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res. 2011;21:658–64.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lee JR, Srour M, Kim D, Hamdan FF, Lim SH, Brunel-Guitton C, Décarie JC, Rossignol E, Mitchell GA, Schreiber A, Moran R, Van Haren K, Richardson R, Nicolai J, Oberndorff KMEJ, Wagner JD, Boycott KM, Rahikkala E, Junna N, Tyynismaa H, Cuppen I, Verbeek NE, Stumpel CTRM, Willemsen MA, de Munnik SA, Rouleau GA, Kim E, Kamsteeg EJ, Kleefstra T, Michaud JL. De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Hum Mutat. 2015;36:69–78.Google Scholar
  32. 32.
    • Cheon CK, Lim SH, Kim YM, Kim D, Lee NY, Yoon TS, et al. Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Sci Rep. 2017;7:12527 In silico and in vitro experiments showing that heterozygous missense mutations affecting the conserved motor domain of KIF1A act through a dominant-negative effect on the wild-type protein. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Khan TN, Klar J, Tariq M, Anjum Baig S, Malik NA, Yousaf R, et al. Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation. Eur J Hum Genet. 2014;22:1180–4.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Sánchez-Ferrero E, Coto E, Beetz C, Gámez J, Corao A, Díaz M, et al. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet. 2013;83:257–62.PubMedCrossRefGoogle Scholar
  35. 35.
    • Klebe S, Depienne C, Gerber S, Challe G, Anheim M, Charles P, et al. SPG7 Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain. 2012;135(Pt 10):2980–93 The authors show that heterozygous mutations in SPG7 can be associated with isolated autosomal dominant optic atrophy or late-onset cerebellar ataxia, whereas this gene is traditionally considered to cause recessive hereditary spastic ataxia. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rydning SL, Dudesek A, Rimmele F, Funke C, Krüger S, Biskup S, et al. A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia. Eur J Neurol. 2018;25(7):943–e71.PubMedCrossRefGoogle Scholar
  37. 37.
    Matthews AM, Tarailo-Graovac M, Price EM, Blydt-Hansen I, Ghani A, Drögemöller BI, et al. A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder. Eur J Med Genet. 2017;60(10):548–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Santorelli FM, Patrono C, Fortini D, Tessa A, Comanducci G, Bertini E, et al. Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene mutation. Neurology. 2000;55:702–5.PubMedCrossRefGoogle Scholar
  39. 39.
    • Parodi L, Fenu S, Barbier M, Banneau G, Duyckaerts C, Tezenas du Montcel S, Monin ML, Ait Said S, Guegan J, Tallaksen CME, Sablonniere B, Brice A, Stevanin G, Depienne C, Durr A, on behalf of the SPATAX network. Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain. 2018 (advance online). This work reports the largest cohort of SPG4 patients ( n = 842 individuals) and reveals that onset occurs significantly earlier in missense mutation carriers and that penetrance is lower in women despite a greater disease severity in female patients. Google Scholar
  40. 40.
    Beetz C, Schüle R, Deconinck T, Tran-Viet KN, Zhu H, Kremer BPH, et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain. 2008;131:1078–86.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Musacchio T, Zaum A-K, Üçeyler N, Sommer C, Pfeifroth N, Reiners K, et al. ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia. J Neurol. 2017;264:11–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004;36:271–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Schickel J, Pamminger T, Ehrsam A, Münch S, Huang X, Klopstock T, et al. Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. Eur J Neurol. 2007;14:1322–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Bouhlal Y, Amouri R, El Euch-Fayeche G, Hentati F. Autosomal recessive spastic ataxia of Charlevoix-Saguenay: an overview. Parkinsonism Relat Disord. 2011;17(6):418–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Gregianin E1, Vazza G, Scaramel E, Boaretto F, Vettori A, Leonardi E, et al. A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy. Eur J Neurol. 2013;20(11):1486–91.PubMedGoogle Scholar
  46. 46.
    Martin E, Schüle R, Smets K, Rastetter A, Boukhris A, Loureiro JL, et al. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013;92:238–44.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, et al. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013;92(2):245–51.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016;139(Pt 7):1904–18.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Rydning SL, Backe PH, Sousa MML, Iqbal Z, Øye AM, Sheng Y, et al. Novel UCHL1 mutations reveal new insights into ubiquitin processing. Hum Mol Genet. 2017;26(6):1031–40.PubMedCrossRefGoogle Scholar
  50. 50.
    Bouwkamp CG, Afawi Z, Fattal-Valevski A, Krabbendam IE, Rivetti S, Masalha R, et al. ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia. Neurol Genet. 2018;4(2):e223.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Marelli C, Hamel C, Quiles M, Carlander B, Larrieu L, Delettre C, et al. ACO2 mutations: a novel phenotype associating severe optic atrophy and spastic paraplegia. Neurol Genet. 2018;4(2):e225.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39:366–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591–8.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Hamdan FF, Gauthier J, Araki Y, Lin D-T, Yoshizawa Y, Higashi K, et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011;88:306–16.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Riviere J-B, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, et al. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011;89:219–30.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Klebe S, Lossos A, Azzedine H, Mundwiller E, Sheffer R, Gaussen M, et al. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. Eur J Hum Genet. 2012;20:645–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Magen D, Georgopoulos C, Bross P, Ang D, Segev Y, Goldsher D, et al. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet. 2008;83(1):30–42.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ishiura H, Sako W, Yoshida M, Kawarai T, Tanabe O, Goto J, et al. The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. Am J Hum Genet. 2012;91(2):320–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, et al. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc Natl Acad Sci U S A. 2013;110(13):5091–6.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Elsayed LEO, Mohammed IN, Hamed AAA, Elseed MA, Johnson A, Mairey M, et al. Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan. Eur J Hum Genet. 2017;25:100–10.CrossRefGoogle Scholar
  62. 62.
    • Coarelli G, Schule R, van de Warrenburg BPC, De Jonghe P, Ewenczyk C, Martinuzzi A, et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 SPG7 patients. Neurology. 2019 (in press). The authors report the largest series of cases with SPG7 mutations. They confirm that ataxia is more frequently associated with missense variants, particularly p.A510V, whereas spasticity is more frequently associated with truncating mutations. A subset of this study has been published in the abstracts of the International Congress of Parkinson's disease and movement disorders 2017 (Abstract in MOv Dis. 2017;32(Suppl 2): 780.Google Scholar
  63. 63.
    • Synofzik M, Gonzalez MA, Marques Lourenço C, Coutelier M, Haack TB, Rebelo A, et al. PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014;137:69–77 This study shows that PNPLA6 mutations are associated with a wide range of phenotypes. PubMedCrossRefGoogle Scholar
  64. 64.
    Ebbing B, Mann K, Starosta A, Jaud J, Schöls L, Schüle R, et al. Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum Mol Genet. 2008;17:1245–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Caballero Oteyza A, Battaloğlu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, et al. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014;82:2007–16.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    • Duchesne A, Vaiman A, Frah M, Floriot S, Rodriguez S, Desmazières A, et al. KIF1C loss of function disturbs oligodendrocyte plasma membrane in progressive ataxia of Charolais cattle and provides a reliable model for spastic ataxia in human. PLoS Genet. 2018;14(8):e1007550 KIF1C loss of function in Charolais cattle leads to spastic ataxia due to a demyelinating process resulting from oligodendrocyte dysfunction. PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing. J Cell Biol. 2007;176:995–1005.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009;10:42–56.PubMedCrossRefGoogle Scholar
  69. 69.
    Park SH, Zhu PP, Parker RL, Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest. 2010;120:1097–110.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Tarrade A, Fassier C, Courageot S, Charvin D, Vitte J, Peris L, et al. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum Mol Genet. 2006;15:3544–58.PubMedCrossRefGoogle Scholar
  71. 71.
    Errico A, Claudiani P, D'Addio M, Rugarli EI. Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon. Hum Mol Genet. 2004;13:2121–32.PubMedCrossRefGoogle Scholar
  72. 72.
    Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by spastin-mediated microtubule severing. J Cell Biol. 2005;168:599–606.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Trotta N, Orso G, Rossetto MG, Daga A, Broadie K. The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr Biol. 2004;14:1135–47.PubMedCrossRefGoogle Scholar
  74. 74.
    Sherwood NT, Sun Q, Xue M, Zhang B, Zinn K. Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol. 2004;2:e429.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Matsushita-Ishiodori Y, Yamanaka K, Ogura T. The C. elegans homologue of the spastic paraplegia protein, spastin, disassembles microtubules. Biochem Biophys Res Commun. 2007;359:157–62.PubMedCrossRefGoogle Scholar
  76. 76.
    Reid E, Connell J, Edwards TL, Duley S, Brown SE, Sanderson CM. The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Hum Mol Genet. 2005;14:19–38.PubMedCrossRefGoogle Scholar
  77. 77.
    Yang D, Rismanchi N, Renvoisé B, Lippincott-Schwartz J, Blackstone C, Hurley JH. Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B. Nat Struct Mol Biol. 2008;15:1278–86.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Evans K, Keller C, Pavur K, Glasgow K, Conn B, Lauring B. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc Natl Acad Sci U S A. 2006;103:10666–71.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sanderson CM, Connell JW, Edwards TL, Bright NA, Duley S, Thompson A, et al. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Hum Mol Genet. 2006;15:307–18.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhu PP, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, et al. Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem. 2003;278:49063–71.PubMedCrossRefGoogle Scholar
  81. 81.
    Zhu PP, Soderblom C, Tao-Cheng JH, Stadler J, Blackstone C. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum Mol Genet. 2006;15:1343–53.PubMedCrossRefGoogle Scholar
  82. 82.
    Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, et al. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007;35:1–13.PubMedCrossRefGoogle Scholar
  83. 83.
    Bakowska JC, Jupille H, Fatheddin P, Puertollano R, Blackstone C. Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. Mol Biol Cell. 2007;18:1683–92.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Robay D, Patel H, Simpson MA, Brown NA, Crosby AH. Endogenous spartin, mutated in hereditary spastic paraplegia, has a complex subcellular localization suggesting diverse roles in neurons. Exp Cell Res. 2006;312:2764–77.PubMedCrossRefGoogle Scholar
  85. 85.
    Hanna MC, Blackstone C. Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1. Neurogenetics. 2009;10:217–28.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Goytain A, Hines RM, El Husseini A, Quamme GA. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. J Biol Chem. 2007;282:8060–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Wang X, Shaw WR, Tsang HT, et al. Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules. Nat Neurosci. 2007;10:177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hadano S, Hand CK, Osuga H, Reid E, O’Kane CJ. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001;29:166–73.PubMedCrossRefGoogle Scholar
  89. 89.
    Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001;29:160–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Deng HX, Zhai H, Fu R, Shi Y, Gorrie GH, Yang Y, et al. Distal axonopathy in an alsin-deficient mouse model. Hum Mol Genet. 2007;16:2911–20.PubMedCrossRefGoogle Scholar
  91. 91.
    Devon RS, Orban PC, Gerrow K, Barbieri MA, Schwab C, Cao LP, et al. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc Natl Acad Sci U S A. 2006;103:9595–600.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Panzeri C, De Palma C, Martinuzzi A, Daga A, De Polo G, Bresolin N, et al. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain. 2006;129:1710–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C. Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum Mol Genet. 2008;17:1591–604.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Orso G, Pendin D, Liu S, Tosetto J, Moss TJ, Faust JE, et al. Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin. Nature. 2009;460:978–83.PubMedCrossRefGoogle Scholar
  95. 95.
    Hu J, Shibata Y, Voss C, Shemesh T, Li Z, Coughlin M, et al. Membrane proteins of the endoplasmic reticulum induce high-curvature tubules. Science. 2008;319:1247–50.PubMedCrossRefGoogle Scholar
  96. 96.
    Evans K, Keller C, Pavur K, Glasgow K, Conn B, Lauring B. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc Natl Acad Sci U S A. 2006;103(28):10666–71.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Park SH, Zhu PP, Parker RL, Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest. 2010;120(4):1097–110.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Schlaitz AL, Thompson J, Wong CCL, Yates JR 3rd, Heald R. REEP3/4 ensure endoplasmic reticulum clearance from metaphase chromatin and proper nuclear envelope architecture. Dev Cell. 2013;26:315–23.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    O’Sullivan NC, Jahn TR, Reid E, O’Kane CJ. Reticulon-like-1, the Drosophila orthologue of the hereditary spastic paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons. Hum Mol Genet. 2012;21:3356–65.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    • Yalçın B, Zhao L, Stofanko M, O’Sullivan NC, Kang ZH, Roost A, et al. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins. Elife. 2017;6 The authors investigated the interplay between reticulon and REEP proteins in axonal ER organization in Drosophila models. Google Scholar
  101. 101.
    • Allison R, Edgar JR, Pearson G, Rizo T, Newton T, Günther S, et al. Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. J Cell Biol. 2017;216:1337–55 This study shows that defects in ER-endosome contacts are responsible for lysosome dysfunctions in several models of HSP. The authors proposed this as a unifying model of axonal degeneration. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Welte MA. Expanding roles for lipid droplets. Curr Biol. 2015;25:R470–81.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Falk J, Rohde M, Bekhite MM, Neugebauer S, Hemmerich P, Kiehntopf M, et al. Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Hum Mutat. 2014;35:497–504.PubMedCrossRefGoogle Scholar
  104. 104.
    Klemm RW, Norton JP, Cole RA, Li CS, Park SH, Crane MM, et al. A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Rep. 2013;3:1465–75.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    •• Papadopoulos C, Orso G, Mancuso G, Herholz M, Gumeni S, Tadepalle N, et al. Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genet. 2015;11:e1005149 Functional studies revealing an unexpected involvement of spastin, the gene product most often affected in HSP, in lipid droplet formation in a Drosophila model of SPG4. PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Renvoisé B, Malone B, Falgairolle M, Munasinghe J, Stadler J, Sibilla C, et al. Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation. Hum Mol Genet. 2016;25:5111–25.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Inloes JM, Hsu KL, Dix MM, Viader A, Masuda K, Takei T, et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc Natl Acad Sci U S A. 2014;111:14924–9.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Renvoisé B, Stadler J, Singh R, Bakowska JC, Blackstone C. Spg20−/− mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Hum Mol Genet. 2012;21:3604–18.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Boukhris A, Schule R, Loureiro JL, Lourenço CM, Mundwiller E, Gonzalez MA, et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet. 2013;93:118–23.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, et al. Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain. 2013;136:3618–24.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Raju D, Schonauer S, Hamzeh H, Flynn KC, Bradke F, Vom Dorp K, et al. Accumulation of glucosylceramide in the absence of the beta-glucosidase GBA2 alters cytoskeletal dynamics. PLoS Genet. 2015;11(3):e1005063.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Schüle R, Siddique T, Deng HX, Yang Y, Donkervoort S, Hansson M, et al. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J Lipid Res. 2010;51:819–23.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Vitner EB, Platt FM, Futerman AH. Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem. 2010;285:20423–7.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis. 2017;2:1–71.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Hirst J, Edgar JR, Esteves T, Darios F, Madeo M, Chang J, et al. Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet. 2015;24:4984–96.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Chang J, Lee S, Blackstone C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest. 2014;124:5249–62.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Khundadze M, Kollmann K, Koch N, Biskup C, Nietzsche S, Zimmer G, et al. A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system. PLoS Genet. 2013;9:e1003988.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Varga RE, Khundadze M, Damme M, Nietzsche S, Hoffmann B, Stauber T, et al. In vivo evidence for lysosome depletion and impaired autophagic clearance in hereditary spastic paraplegia type SPG11. PLoS Genet. 2015;11:e1005454.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Branchu J, Boutry M, Sourd L, Depp M, Leone C, Corriger A, et al. Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Neurobiol Dis. 2017;102:21–37.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    •• Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R, et al. Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration. Cell Rep. 2018;23:3813–26 This study shows that spatacsin is important for lysosome membrane recycling and ganglioside clearance. The accumulation of gangliosides in lysosomes in SPG11 models is deleterious to neurons and its prevention decreases cell death rates in vitro and improves motor phenotype in zebrafish models. PubMedCrossRefGoogle Scholar
  121. 121.
    Onyenwoke RU, Brenman JE. Lysosomal storage diseases-regulating neurodegeneration. J Exp Neurosci. 2015;9:81–91.PubMedGoogle Scholar
  122. 122.
    Yang DS, Stavrides P, Saito M, Kumar A, Rodriguez-Navarro JA, Pawlik M, et al. Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain. 2014;137:3300–18.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Bross P, Naundrup S, Hansen J, Nielsen MN, Christensen JH, Kruhøffer M, et al. The Hsp60-(p.V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo. J Biol Chem. 2008;283:15694–700.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Ferreirinha F, Quattrini A, Pirozzi M, Valsecchi V, Dina G, Broccoli V, et al. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest. 2004;113:231–42.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Lu J, Rashid F, Byrne PC. The hereditary spastic paraplegia protein spartin localises to mitochondria. J Neurochem. 2006;98:1908–19.PubMedCrossRefGoogle Scholar
  126. 126.
    Yang Y, Liu W, Fang Z, Shi J, Che F, He C, et al. A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. Hum Mutat. 2016;37:165–9.PubMedCrossRefGoogle Scholar
  127. 127.
    • Lavie J, Serrat R, Bellance N, Courtand G, Dupuy JW, Tesson C, et al. Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Hum Mol Genet. 2017;26(4):674–85 The authors report a secondary mitochondrial alteration in the cells of patients with REEP1 mutations, due to abnormal interactions between REEP1 and a mitochondrial protein. PubMedGoogle Scholar
  128. 128.
    Fransen E, D'Hooge R, Van Camp G, Verhoye M, Sijbers J, Reyniers E, et al. L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns. Hum Mol Genet. 1998;7(6):999–1009.PubMedCrossRefGoogle Scholar
  129. 129.
    Groh J, Friedman HC, Orel N, Ip CW, Fischer S, Spahn I, et al. Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations. Hum Mol Genet. 2016;25(21):4686–702.PubMedGoogle Scholar
  130. 130.
    •• Fassier C, Hutt JA, Scholpp S, Lumsden A, Giros B, Nothias F, et al. Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci. 2010;13(11):1380–7 Atlastin regulates BMP receptor trafficking and the inhibition of BMP signaling rescues motor defects and spinal motor axon abnormalities in zebrafish mimicking SPG3. PubMedCrossRefGoogle Scholar
  131. 131.
    Martin E, Yanicostas C, Rastetter A, Alavi-Naini SM, Maouedj A, Kabashi E, et al. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Neurobiol Dis. 2012;48:299–308.PubMedCrossRefGoogle Scholar
  132. 132.
    Fan Y, Wali G, Sutharsan R, Bellette B, Crane DI, Sue CM, et al. Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in hereditary spastic paraplegia. Biol Open. 2014;3(6):494–502.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    • Julien C, Lissouba A, Madabattula S, Fardghassemi Y, Rosenfelt C, Androschuk A, et al. Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms. Hum Mol Genet. 2016;25(6):1088–99 The screening of chemical compounds modulating ER stress in various models of SPG4 identified molecules that attenuated locomotor defects. PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Orso G, Martinuzzi A, Rossetto MG, Sartori E, Feany M, Daga A. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. J Clin Invest. 2005;115:3026–34.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Pirozzi M, Quattrini A, Andolfi G, Dina G, Malaguti MC, Auricchio A, et al. Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia. J Clin Invest. 2006;116:202–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Zhu PP, Denton KR, Pierson TM, Li XJ, Blackstone C. Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. Hum Mol Genet. 2014;23(21):5638–48.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    •• Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, et al. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017;140(12):3112–27 The authors demonstrate a correlation between serum and CSF oxysterol concentrations in SPG5 patients. The use of atorvastatin reduced oxysterols in serum but not in CSF, whereas the placebo had no effect. PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    • Marelli C, Lamari F, Rainteau D, Lafourcade A, Banneau G, Humbert L, et al. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain. 2018, 141:72–84 A phase II clinical trial in 12 patients showed that the combination of atorvastatin and chenodeoxycholic acid lowered plasma oxysterol concentration and improved bile-acid profile in SPG5 patients. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Maxime Boutry
    • 1
    • 2
    • 3
  • Sara Morais
    • 1
    • 2
    • 4
  • Giovanni Stevanin
    • 1
    • 2
    Email author
  1. 1.Institut du Cerveau et de la Moelle épinièreSorbonne Université UMR_S1127ParisFrance
  2. 2.Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE)Paris Sciences Lettres (PSL) Research UniversityParisFrance
  3. 3.Cell Biology ProgramHospital for Sick ChildrenTorontoCanada
  4. 4.UnIGENe, Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal

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