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

Kyle R. Denton, Chongchong Xu, Harsh Shah, Xue-Jun Li

PDF(980 KB)
PDF(980 KB)
Front. Biol. ›› 2016, Vol. 11 ›› Issue (5) : 339-354. DOI: 10.1007/s11515-016-1416-0
REVIEW
REVIEW

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

Author information +
History +

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

Cite this article

Download citation ▾
Kyle R. Denton, Chongchong Xu, Harsh Shah, Xue-Jun Li. Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells. Front. Biol., 2016, 11(5): 339‒354 https://doi.org/10.1007/s11515-016-1416-0

References

[1]
Ben-David U, Kopper O, Benvenisty N (2012). Expanding the boundaries of embryonic stem cells. Cell Stem Cell, 10(6): 666–677
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[3]
Blackstone C (2012). Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci, 35(1): 25–47
CrossRef Pubmed Google scholar
[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
Pubmed
[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
CrossRef Pubmed Google scholar
[6]
Chen H, Chan D C (2009). Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet, 18(R2): R169–R176
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[15]
Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[21]
Fink J K (2006). Hereditary spastic paraplegia. Curr Neurol Neurosci Rep, 6(1): 65–76
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[23]
Grove E A, Fukuchi-Shimogori T (2003). Generating the cerebral cortical area map. Annu Rev Neurosci, 26(1): 355–380
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[27]
Halliwell B (2014). Cell culture, oxidative stress, and antioxidants: avoiding pitfalls. Biomed J, 37(3): 99–105
Pubmed
[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
CrossRef Pubmed Google scholar
[29]
Harding A E (1983). Classification of the hereditary ataxias and paraplegias. Lancet, 1(8334): 1151–1155
CrossRef Pubmed Google scholar
[30]
Harding A E (1993). Hereditary spastic paraplegias. Semin Neurol, 13(4): 333–336
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[36]
Hollenbeck P J (2005). Mitochondria and neurotransmission: evacuating the synapse. Neuron, 47(3): 331–333
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[41]
Kiskinis E, Eggan K (2010). Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest, 120(1): 51–59
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[44]
Knott A B, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008). Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci, 9(7): 505–518
CrossRef Pubmed Google scholar
[45]
Kola I, Landis J (2004). Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov, 3(8): 711–715
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[54]
Lunn M R, Wang C H (2008). Spinal muscular atrophy. Lancet, 371(9630): 2120–2133
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[60]
Manfredi G, Xu Z (2005). Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion, 5(2): 77–87
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[67]
Moss T J, Daga A, McNew J A (2011). Fusing a lasting relationship between ER tubules. Trends Cell Biol, 21(7): 416–423
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[76]
Okita K, Ichisaka T, Yamanaka S (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151): 313–317
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[85]
Reid E (2003). Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet, 40(2): 81–86
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[101]
Walther T C, Farese R V Jr (2012). Lipid droplets and cellular lipid metabolism. Annu Rev Biochem, 81(1): 687–714
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
Pubmed
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[113]
Zhang S C (2006). Neural subtype specification from embryonic stem cells. Brain Pathol, 16(2): 132–142
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar
[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
CrossRef Pubmed Google scholar

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.

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg
PDF(980 KB)

Accesses

Citations

Detail

Sections
Recommended

/