Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells

Abstract

BACKGROUND: Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia (HSP). Since the discovery of the first HSP gene, SPAST that encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects.

METHODS: In this article, we will first review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions.

RESULTS: HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects.

CONCLUSIONS: These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.

Keywords

HSP / axonal degeneration / pluripotent stem cells / spastin / atlastin-1

References

[1] Ben-David U, Kopper O, Benvenisty N (2012). Expanding the boundaries of embryonic stem cells. Cell Stem Cell, 10(6): 666–677

[2] Bilican B, Serio A, Barmada S J, Nishimura A L, Sullivan G J, Carrasco M, Phatnani H P, Puddifoot C A, Story D, Fletcher J, Park I H, Friedman B A, Daley G Q, Wyllie D J, Hardingham G E, Wilmut I, Finkbeiner S, Maniatis T, Shaw C E, Chandran S (2012). Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA, 109(15): 5803–5808

[3] Blackstone C (2012). Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci, 35(1): 25–47

[4] Blackstone C, O’Kane C J, Reid E (2011). Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci, 12(1): 31–42

[5] Boulting G L, Kiskinis E, Croft G F, Amoroso M W, Oakley D H, Wainger B J, Williams D J, Kahler D J, Yamaki M, Davidow L, Rodolfa C T, Dimos J T, Mikkilineni S, MacDermott A B, Woolf C J, Henderson C E, Wichterle H, Eggan K (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol, 29(3): 279–286

[6] Chen H, Chan D C (2009). Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet, 18(R2): R169–R176

[7] Claudiani P, Riano E, Errico A, Andolfi G, Rugarli E I (2005). Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. Exp Cell Res, 309(2): 358–369

[8] Crosby A H, Proukakis C (2002). Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet, 71(5): 1009–1016

[9] De Vos K J, Grierson A J, Ackerley S, Miller C C (2008). Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci, 31(1): 151–173

[10] Deluca G C, Ebers G C, Esiri M M (2004). The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol, 30(6): 576–584

[11] Denton K R, Lei L, Grenier J, Rodionov V, Blackstone C, Li X J (2014). Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells, 32(2): 414–423

[12] Dimos J T, Rodolfa K T, Niakan K K, Weisenthal L M, Mitsumoto H, Chung W, Croft G F, Saphier G, Leibel R, Goland R, Wichterle H, Henderson C E, Eggan K (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893): 1218–1221

[13] Ebert A D, Yu J, Rose F F Jr, Mattis V B, Lorson C L, Thomson J A, Svendsen C N (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457(7227): 277–280

[14] Errico A, Ballabio A, Rugarli E I (2002). Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet, 11(2): 153–163

[15] Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156

[16] Falk J, Rohde M, Bekhite M M, Neugebauer S, Hemmerich P, Kiehntopf M, Deufel T, Hübner C A, Beetz C (2014). Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Hum Mutat, 35(4): 497–504

[17] Fan Y, Wali G, Sutharsan R, Bellette B, Crane D I, Sue C M, Mackay-Sim A (2014). Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia. Biol Open, 3(6): 494–502

[18] Fassier C, Hutt J A, Scholpp S, Lumsden A, Giros B, Nothias F, Schneider-Maunoury S, Houart C, Hazan J (2010). Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci, 13(11): 1380–1387

[19] Fink J K (1993). Hereditary Spastic Paraplegia Overview. In: Pagon R A, Adam M P, Ardinger H H, Wallacc S E, Amemiya A, BeauL J H, Bird T D, Fong C T, Mefford H C, Smith R J H, Stephens K, Eds. Gene Reviews [Internet]. Seatlle (WA): University of Washington, Seattle 1993–2016

[20] Fink J K (2003). Advances in the hereditary spastic paraplegias. Exp Neurol, 184(Suppl 1): S106–S110

[21] Fink J K (2006). Hereditary spastic paraplegia. Curr Neurol Neurosci Rep, 6(1): 65–76

[22] Fonknechten N, Mavel D, Byrne P, Davoine C S, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder J M, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud’homme J F, Weissenbach J, Dürr A, Hazan J (2000). Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet, 9(4): 637–644

[23] Grove E A, Fukuchi-Shimogori T (2003). Generating the cerebral cortical area map. Annu Rev Neurosci, 26(1): 355–380

[24] Guha P, Morgan J W, Mostoslavsky G, Rodrigues N P, Boyd A S (2013). Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell, 12(4): 407–412

[25] Guidubaldi A, Piano C, Santorelli F M, Silvestri G, Petracca M, Tessa A, Bentivoglio A R (2011). Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism. Mov Disord, 26(3): 553–556

[26] Hallett P J, Deleidi M, Astradsson A, Smith G A, Cooper O, Osborn T M, Sundberg M, Moore M A, Perez-Torres E, Brownell A L, Schumacher J M, Spealman R D, Isacson O (2015). Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell, 16(3): 269–274

[27] Halliwell B (2014). Cell culture, oxidative stress, and antioxidants: avoiding pitfalls. Biomed J, 37(3): 99–105

[28] Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli F M, Mhiri C, Brice A, Stevanin G (2008). Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet, 82(4): 992–1002

[29] Harding A E (1983). Classification of the hereditary ataxias and paraplegias. Lancet, 1(8334): 1151–1155

[30] Harding A E (1993). Hereditary spastic paraplegias. Semin Neurol, 13(4): 333–336

[31] Havlicek S, Kohl Z, Mishra H K, Prots I, Eberhardt E, Denguir N, Wend H, Plötz S, Boyer L, Marchetto M C, Aigner S, Sticht H, Groemer T W, Hehr U, Lampert A, Schlötzer-Schrehardt U, Winkler J, Gage F H, Winner B (2014). Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients’ neurons. Hum Mol Genet, 23(10): 2527–2541

[32] Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine C S, Cruaud C, Dürr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder J M, Prud’homme J F, Brice A, Fontaine B, Heilig B, Weissenbach J (1999). Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet, 23(3): 296–303

[33] Hedera P, Eldevik O P, Maly P, Rainier S, Fink J K (2005). Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. Neuroradiology, 47(10): 730–734

[34] Hirst J, Borner G H, Edgar J, Hein M Y, Mann M, Buchholz F, Antrobus R, Robinson M S (2013). Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15. Mol Biol Cell, 24(16): 2558–2569

[35] Hockemeyer D, Wang H, Kiani S, Lai C S, Gao Q, Cassady J P, Cost G J, Zhang L, Santiago Y, Miller J C, Zeitler B, Cherone J M, Meng X, Hinkley S J, Rebar E J, Gregory P D, Urnov F D, Jaenisch R (2011). Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol, 29(8): 731–734

[36] Hollenbeck P J (2005). Mitochondria and neurotransmission: evacuating the synapse. Neuron, 47(3): 331–333

[37] Hu J, Shibata Y, Zhu P P, Voss C, Rismanchi N, Prinz W A, Rapoport T A, Blackstone C (2009). A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell, 138(3): 549–561

[38] Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna J A, Charpentier E (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096): 816–821

[39] Kanekura K, Suzuki H, Aiso S, Matsuoka M (2009). ER stress and unfolded protein response in amyotrophic lateral sclerosis. Mol Neurobiol, 39(2): 81–89

[40] Kasher P R, De Vos K J, Wharton S B, Manser C, Bennett E J, Bingley M, Wood J D, Milner R, McDermott C J, Miller C C, Shaw P J, Grierson A J (2009). Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. J Neurochem, 110(1): 34–44

[41] Kiskinis E, Eggan K (2010). Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest, 120(1): 51–59

[42] Kiskinis E, Sandoe J, Williams L A, Boulting G L, Moccia R, Wainger B J, Han S, Peng T, Thams S, Mikkilineni S, Mellin C, Merkle F T, Davis-Dusenbery B N, Ziller M, Oakley D, Ichida J, Di Costanzo S, Atwater N, Maeder M L, Goodwin M J, Nemesh J, Handsaker R E, Paull D, Noggle S, McCarroll S A, Joung J K, Woolf C J, Brown R H, Eggan K (2014). Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell, 14(6): 781–795

[43] Klemm R W, Norton J P, Cole R A, Li C S, Park S H, Crane M M, Li L, Jin D, Boye-Doe A, Liu T Y, Shibata Y, Lu H, Rapoport T A, Farese R V Jr, Blackstone C, Guo Y, Mak H Y (2013). A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Reports, 3(5): 1465–1475

[44] Knott A B, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008). Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci, 9(7): 505–518

[45] Kola I, Landis J (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov, 3(8): 711–715

[46] Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein W L, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013). Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell, 12(4): 487–496

[47] Lee H, Shamy G A, Elkabetz Y, Schofield C M, Harrsion N L, Panagiotakos G, Socci N D, Tabar V, Studer L (2007). Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons. Stem Cells, 25(8): 1931–1939

[48] Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frézal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995). Identification and characterization of a spinal muscular atrophy-determining gene. Cell, 80(1): 155–165

[49] Li X J, Du Z W, Zarnowska E D, Pankratz M, Hansen L O, Pearce R A, Zhang S C (2005). Specification of motoneurons from human embryonic stem cells. Nat Biotechnol, 23(2): 215–221

[50] Lindsey J C, Lusher M E, McDermott C J, White K D, Reid E, Rubinsztein D C, Bashir R, Hazan J, Shaw P J, Bushby K M (2000). Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis. J Med Genet, 37(10): 759–765

[51] Ling S C, Polymenidou M, Cleveland D W (2013). Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron, 79(3): 416–438

[52] Liu G H, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla R D, Dubova I, Thompson J, Yates J 3rd, Esteban C R, Sancho-Martinez I, Izpisua Belmonte J C (2012). Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 491(7425): 603–607

[53] Lumb J H, Connell J W, Allison R, Reid E (2012). The AAA ATPase spastin links microtubule severing to membrane modelling. Biochim Biophys Acta, 1823(1): 192–197

[54] Lunn M R, Wang C H (2008). Spinal muscular atrophy. Lancet, 371(9630): 2120–2133

[55] Ly CV, Verstreken P (2006) Mitochondria at the synapse. The Neuroscientist: a review journal bringing neurobiology, neurology and psychiatry 12:291–299.

[56] Ma L, Hu B, Liu Y, Vermilyea S C, Liu H, Gao L, Sun Y, Zhang X, Zhang S C (2012). Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell, 10(4): 455–464

[57] Magrané J, Cortez C, Gan W B, Manfredi G (2014). Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet, 23(6): 1413–1424

[58] Mali P, Yang L, Esvelt K M, Aach J, Guell M, DiCarlo J E, Norville J E, Church G M (2013). RNA-guided human genome engineering via Cas9. Science, 339(6121): 823–826

[59] Mancuso G, Rugarli E I (2008). A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. BMC Biol, 6(1): 31

[60] Manfredi G, Xu Z (2005). Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion, 5(2): 77–87

[61] Martin G R (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA, 78(12): 7634–7638

[62] Miller J C, Tan S, Qiao G, Barlow K A, Wang J, Xia D F, Meng X, Paschon D E, Leung E, Hinkley S J, Dulay G P, Hua K L, Ankoudinova I, Cost G J, Urnov F D, Zhang H S, Holmes M C, Zhang L, Gregory P D, Rebar E J (2011). A TALE nuclease architecture for efficient genome editing. Nat Biotechnol, 29(2): 143–148

[63] Miller J D, Ganat Y M, Kishinevsky S, Bowman R L, Liu B, Tu E Y, Mandal P K, Vera E, Shim J W, Kriks S, Taldone T, Fusaki N, Tomishima M J, Krainc D, Milner T A, Rossi D J, Studer L (2013). Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell, 13(6): 691–705

[64] Mishra HK, Prots I, Havlicek S, Kohl Z, Perez-Branguli F, Boerstler T, Anneser L, Minakaki G, Wend H, Hampl M, Leone M, Bruckner M, Klucken J, Reis A, Boyer L, Schuierer G, Behrens J, Lampert A, Engel FB, Gage FH, Winkler J, Winner B (2016) GSK3ss-dependent dysregulation of neurodevelopment in SPG11-patient iPSC model. Ann Neurol.

[65] Montague K, Malik B, Gray A L, La Spada A R, Hanna M G, Szabadkai G, Greensmith L (2014). Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy. Brain, 137(Pt 7): 1894–1906

[66] Montenegro G, Rebelo A P, Connell J, Allison R, Babalini C, D’Aloia M, Montieri P, Schüle R, Ishiura H, Price J, Strickland A, Gonzalez M A, Baumbach-Reardon L, Deconinck T, Huang J, Bernardi G, Vance J M, Rogers M T, Tsuji S, De Jonghe P, Pericak-Vance M A, Schöls L, Orlacchio A, Reid E, Züchner S (2012). Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest, 122(2): 538–544

[67] Moss T J, Daga A, McNew J A (2011). Fusing a lasting relationship between ER tubules. Trends Cell Biol, 21(7): 416–423

[68] Murmu R P, Martin E, Rastetter A, Esteves T, Muriel M P, El Hachimi K H, Denora P S, Dauphin A, Fernandez J C, Duyckaerts C, Brice A, Darios F, Stevanin G (2011). Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia. Mol Cell Neurosci, 47(3): 191–202

[69] Murry C E, Keller G (2008). Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell, 132(4): 661–680

[70] Nadar V C, Ketschek A, Myers K A, Gallo G, Baas P W (2008). Kinesin-5 is essential for growth-cone turning. Curr Biol, 18(24): 1972–1977

[71] Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Dürr A, Brice A (2006). SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology, 66(1): 112–114

[72] Nguyen H N, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch R E, Langston W, Palmer T D, Pera R R (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell, 8(3): 267–280

[73] Niu J, Zhang B, Chen H (2014). Applications of TALENs and CRISPR/Cas9 in human cells and their potentials for gene therapy. Mol Biotechnol, 56(8): 681–688

[74] Novarino G, Fenstermaker A G, Zaki M S, Hofree M, Silhavy J L, Heiberg A D, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama J Y, Abdel-Salam G M, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud I G, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu P S, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa M Y, Schroth J, Spencer E G, Rosti R O, Akizu N, Vaux K K, Johansen A, Koh A A, Megahed H, Durr A, Brice A, Stevanin G, Gabriel S B, Ideker T, Gleeson J G (2014). Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science, 343(6170): 506–511

[75] O’Leary D D, Nakagawa Y (2002). Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr Opin Neurobiol, 12(1): 14–25

[76] Okita K, Ichisaka T, Yamanaka S (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151): 313–317

[77] Pantakani D V, Swapna L S, Srinivasan N, Mannan A U (2008). Spastin oligomerizes into a hexamer and the mutant spastin (E442Q) redistribute the wild-type spastin into filamentous microtubule. J Neurochem, 106(2): 613–624

[78] Park I H, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch M W, Cowan C, Hochedlinger K, Daley G Q (2008). Disease-specific induced pluripotent stem cells. Cell, 134(5): 877–886

[79] Park S, Lee K S, Lee Y J, Shin H A, Cho H Y, Wang K C, Kim Y S, Lee H T, Chung K S, Kim E Y, Lim J (2004). Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci Lett, 359(1-2): 99–103

[80] Park S H, Zhu P P, Parker R L, Blackstone C (2010). Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest, 120(4): 1097–1110

[81] Pérez-Brangulí F, Mishra H K, Prots I, Havlicek S, Kohl Z, Saul D, Rummel C, Dorca-Arevalo J, Regensburger M, Graef D, Sock E, Blasi J, Groemer T W, Schlötzer-Schrehardt U, Winkler J, Winner B (2014). Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. Hum Mol Genet, 23(18): 4859–4874

[82] Perrier A L, Tabar V, Barberi T, Rubio M E, Bruses J, Topf N, Harrison N L, Studer L (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA, 101(34): 12543–12548

[83] Piaceri I, Rinnoci V, Bagnoli S, Failli Y, Sorbi S (2012). Mitochondria and Alzheimer’s disease. J Neurol Sci, 322(1-2): 31–34

[84] Polleux F, Dehay C, Goffinet A, Kennedy H (2001). Pre- and post-mitotic events contribute to the progressive acquisition of area-specific connectional fate in the neocortex. Cereb Cortex, 11(11): 1027–1039

[85] Reid E (2003). Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet, 40(2): 81–86

[86] Renvoisé B, Blackstone C (2010). Emerging themes of ER organization in the development and maintenance of axons. Curr Opin Neurobiol, 20(5): 531–537

[87] Reubinoff B E, Itsykson P, Turetsky T, Pera M F, Reinhartz E, Itzik A, Ben-Hur T (2001). Neural progenitors from human embryonic stem cells. Nat Biotechnol, 19(12): 1134–1140

[88] Roy N S, Cleren C, Singh S K, Yang L, Beal M F, Goldman S A (2006). Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med, 12(11): 1259–1268

[89] Salinas S, Proukakis C, Crosby A, Warner T T (2008). Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol, 7(12): 1127–1138

[90] Schicks J, Synofzik M, Pétursson H, Huttenlocher J, Reimold M, Schöls L, Bauer P (2011). Atypical juvenile parkinsonism in a consanguineous SPG15 family. Mov Disord, 26(3): 564–566

[91] Singh Roy N, Nakano T, Xuing L, Kang J, Nedergaard M, Goldman S A (2005). Enhancer-specified GFP-based FACS purification of human spinal motor neurons from embryonic stem cells. Exp Neurol, 196(2): 224–234

[92] Soderblom C, Blackstone C (2006). Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther, 109(1-2): 42–56

[93] Solowska J M, Morfini G, Falnikar A, Himes B T, Brady S T, Huang D, Baas P W (2008). Quantitative and functional analyses of spastin in the nervous system: implications for hereditary spastic paraplegia. J Neurosci, 28(9): 2147–2157

[94] Stevanin G, Santorelli F M, Azzedine H, Coutinho P, Chomilier J, Denora P S, Martin E, Ouvrard-Hernandez A M, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro J L, Elleuch N, Confavreux C, Cruz V T, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A (2007). Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet, 39(3): 366–372

[95] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861–872

[96] Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663–676

[97] Tarrade A, Fassier C, Courageot S, Charvin D, Vitte J, Peris L, Thorel A, Mouisel E, Fonknechten N, Roblot N, Seilhean D, Diérich A, Hauw J J, Melki J (2006). 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, 15(24): 3544–3558

[98] Thomson J A, Itskovitz-Eldor J, Shapiro S S, Waknitz M A, Swiergiel J J, Marshall V S, Jones J M (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391): 1145–1147

[99] Valente E M, Abou-Sleiman P M, Caputo V, Muqit M M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A R, Healy D G, Albanese A, Nussbaum R, Gonz�lez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W P, Latchman D S, Harvey R J, Dallapiccola B, Auburger G, Wood N W (2004). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science, 304(5674): 1158–1160

[100] Vidal R, Caballero B, Couve A, Hetz C (2011). Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease. Curr Mol Med, 11(1): 1–12

[101] Walther T C, Farese R V Jr (2012). Lipid droplets and cellular lipid metabolism. Annu Rev Biochem, 81(1): 687–714

[102] Wang D, Lagerstrom R, Sun C, Bishof L, Valotton P, Götte M (2010). HCA-vision: Automated neurite outgrowth analysis. J Biomol Screen, 15(9): 1165–1170

[103] Wang H, Yang H, Shivalila C S, Dawlaty M M, Cheng A W, Zhang F, Jaenisch R (2013a). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4): 910–918

[104] Wang Z B, Zhang X, Li X J (2013b). Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy. Cell Res, 23(3): 378–393

[105] Wilfling F, Wang H, Haas J T, Krahmer N, Gould T J, Uchida A, Cheng J X, Graham M, Christiano R, Fröhlich F, Liu X, Buhman K K, Coleman R A, Bewersdorf J, Farese R V Jr, Walther T C (2013). Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell, 24(4): 384–399

[106] Xu C C, Denton K R, Wang Z B, Zhang X, Li X J (2016). Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy. Dis Model Mech, 9(1): 39–49

[107] Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011). Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet, 20(23): 4530–4539

[108] Yan Y, Yang D, Zarnowska E D, Du Z, Werbel B, Valliere C, Pearce R A, Thomson J A, Zhang S C (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23(6): 781–790

[109] Yang Y M, Gupta S K, Kim K J, Powers B E, Cerqueira A, Wainger B J, Ngo H D, Rosowski K A, Schein P A, Ackeifi C A, Arvanites A C, Davidow L S, Woolf C J, Rubin L L (2013). A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell, 12(6): 713–726

[110] Yu J, Vodyanik M A, Smuga-Otto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858): 1917–1920

[111] Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z, Park J W, Zhan S, Kronenberg M S, Lichtler A, Liu H X, Chen F P, Yue L, Li X J, Xu R H (2010). Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS ONE, 5(7): e11853

[112] Zhang N, An M C, Montoro D, Ellerby L M (2010). Characterization of Human Huntington’s Disease Cell Model from Induced Pluripotent Stem Cells. PLoS Curr, 2: RRN1193

[113] Zhang S C (2006). Neural subtype specification from embryonic stem cells. Brain Pathol, 16(2): 132–142

[114] Zhang S C, Wernig M, Duncan I D, Brüstle O, Thomson J A (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol, 19(12): 1129–1133

[115] Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber C H, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink J K (2001). Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet, 29(3): 326–331

[116] Zhu P P, Denton K R, Pierson T M, Li X J, Blackstone C (2014). Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. Hum Mol Genet, 23(21): 5638–5648

[117] 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(49): 49063–49071

Acknowledgments

This work has been supported by the Blazer Foundation and a NIH grant (R21NS089042) to X.J.L.

Compliance with ethics guidelines

Kyle Denton, Chongchong Xu, Harsh Shah, and Xue-Jun Li declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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2016 Higher Education Press and Springer-Verlag Berlin Heidelberg