References

ssmu

Бюллетень сибирской медицины

Bulletin of Siberian Medicine

1682-03631819-3684

Siberian State Medical University, the Ministry of Healthcare of the Russian Federation

10.20538/1682-0363-2021-3-193-202

ssmu-4497

Research Article

ОБЗОРЫ И ЛЕКЦИИ

REVIEW AND LECTURES

Генетика семейных форм бокового амиотрофического склероза

Genetics of familial amyotrophic lateral sclerosis

https://orcid.org/0000-0002-7036-5326

Савинова

А. В.

Savinova

A. V.

врач-невролог, ординатор

Россия, 192019, г. Санкт-Петербург, ул. Бехтерева, 3

3, Bekhterev Str., Saint Petersburg, 192019, Russian Federation

https://orcid.org/0000-0002-2840-837X

Шнайдер

Н. А.

Shnayder

N. A.

д-р мед. наук, профессор, вед. науч. сотрудник, отделение персонализированной психиатрии и неврологии; невролог, неврологический центр эпилептологии, нейрогенетики и исследования мозга, Университетская клиника

Россия, 192019, г. Санкт-Петербург, ул. Бехтерева, 3

Россия, 660022, г. Красноярск, ул. Партизана Железняка, 1

3, Bekhterev Str., Saint Petersburg, 192019, Russian Federation

1, Partizana Zheleznyaka Str., Krasnoyarsk, 660022, Russian Federation

https://orcid.org/0000-0003-1874-9434

Насырова

Р. Ф.

Nasyrova

R. F.

д-р мед. наук, гл. науч. сотрудник, руководитель отделения персонализированной психиатрии и неврологии; гл. науч. сотрудник, научно-исследовательская лаборатория OpenLab «Генные и клеточные технологии», Институт фундаментальной медицины и биологии

Россия, 192019, г. Санкт-Петербург, ул. Бехтерева, 3

Россия,420008, г. Казань, ул. Кремлевская, 18

3, Bekhterev Str., Saint Petersburg, 192019, Russian Federation

18, Kremlyovskaya Str., Kazan, 420008, Russian Federation

nreginaf77@gmail.com

Национальный медицинский исследовательский центр психиатрии и неврологии (НМИЦ ПН) имени В.М. БехтереваРоссияV.M. Bekhterev National Research Medical Center for Psychiatry and Neurology (V.M. Bekhterev NRMC PN)Russian Federation

Национальный медицинский исследовательский центр психиатрии и неврологии (НМИЦ ПН) имени В.М. Бехтерева; Красноярский государственный медицинский университет (КрасГМУ) имени профессора В.Ф. Войно-ЯсенецкогоРоссияV.M. Bekhterev National Research Medical Center for Psychiatry and Neurology (V.M. Bekhterev NRMC PN); V.F. Voino-Yasenetsky Krasnoyarsk State Medical University (V.F. Voino-Yasenetsky KrasSMU)Russian Federation

Национальный медицинский исследовательский центр психиатрии и неврологии (НМИЦ ПН) имени В.М. Бехтерева; Казанский федеральный университет (КФУ)РоссияV.M. Bekhterev National Research Medical Center for Psychiatry and Neurology (V.M. Bekhterev NRMC PN); Kazan Federal University (KFU)Russian Federation

2021

21102021

203193202

2021

Савинова А.В., Шнайдер Н.А., Насырова Р.Ф.

Savinova A.V., Shnayder N.A., Nasyrova R.F.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://bulletin.ssmu.ru/jour/article/view/4497

Анализируются результаты исследований, отражающих современное представление о генетике семейных форм бокового амиотрофического склероза (сБАС).Проведен поиск полнотекстовых публикаций на русском и английском языках за последнее десятилетие в базах данных eLibrary, PubMed, Web of Science, OMIM, используя ключевые слова «боковой амиотрофический склероз» (БАС), «сБАС», «генетика». Кроме того, в обзор включены более ранние публикации, имеющие исторический интерес.Представлены современные данные, накопленные по четырем самым распространенным генам возникновения сБАС: SOD1, TARDBP, FUS и C9ORF72. Рассмотрена функция этих генов, а также возможные патогенетические механизмы гибели мотонейронов при БАС: митохондриальная дисфункция, глутаматная эксайтотоксичноть, оксидативный стресс, поражение компонентов системы аксонального транспорта, патологическая агрегация нейрофиламентов.По мере развития современных методов молекулярно-генетической диагностики расширяются знания в понимании генетики семейных мультифакторных форм БАС, что важно учитывать в клинической практике врачей-неврологов. Выявление генов, ответственных за возникновение БАС, а также понимание конкретных патогенетических механизмов развития заболевания играют ключевую роль в разработке эффективных терапевтических стратегий.

To analyze results of the studies covering modern scientific views on the genetics of familial amyotrophic lateral sclerosis (FALS).We searched for full-text publications containing the key words “amyotrophic lateral sclerosis”, “FALS”, and “genetics” in the literature for the past 10 years in both Russian and English in eLibrary, PubMed, Web of Science, and OMIM databases. In addition, the review includes earlier publications of historical interest.This review summarizes all existing information on four most widespread genes associated with FALS: SOD1, TARDBP, FUS, and C9ORF72. The review also describes the functions of these genes and possible pathogenetic mechanisms of motor neuron death in amyotrophic lateral sclerosis (ALS), such as mitochondrial dysfunction, oxidative stress, glutamate excitotoxicity, damage to axonal transport components, and pathological neurofilament aggregation.As modern methods of molecular genetic diagnostics evolve, our knowledge about multifactorial FALS genetics expands. This information should be taken into consideration in clinical practice of neurologists. Information about the genes associated with ALS and understanding of particular pathogenetic mechanisms of the disease play a key role in the development of effective therapeutic strategies.

боковой амиотрофический склерозБАСсемейный БАСгенетикаSODFUSTARDBPC9ORF72

amyotrophic lateral sclerosisALSfamilial ALSgeneticsSODFUSTARDBPC9ORF72

References1

Rowland L.P. Amyotrophic lateral sclerosis. Curr. Opin. Neurol. 1994; 7 (4): 310–315. DOI: 10.1097/00019052-199408000-00006.

Chiò A., Logroscino G., Traynor B.J., Collins J., Simeone J.C., Goldstein L.A., White L.A. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013; 41 (2): 118–130. DOI: 10.1159/000351153.

Ingre C., Roos P.M., Piehl F. Risk factors for amyotrophic lateral sclerosis. Clin. Epidemiol. 2015; 7: 181–193. DOI: 10.2147/CLEP.S37505.

Zou Z.Y., Zhou Z.R., Che C.H., Liu C.Y., He R.L., Huang H.P. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry. 2017; 88 (7): 540–549. DOI: 10.1136/jnnp-2016-315018.

Veldink J.H. ALS genetic epidemiology ‘How simplex is the genetic epidemiology of ALS?’ J. Neurol. Neurosurg. Psychiatry. 2017; 88 (7): 537. DOI: 10.1136/jnnp-2016-315469.

DeJesus-Hernandez M., Mackenzie I.R., Boeve BF.., Boxer A.L., Baker M., Rutherford N.J., Nicholson A.M., Finch N.A., Flynn H., Adamson J., Kouri N., Wojtas A., Sengdy P., Hsiung G.Y., Karydas A., Seeley W.W., Josephs K.A., Coppola G., Geschwind D.H., Wszolek Z.K., Feldman H., Knopman D.S., Petersen R.C., Miller B.L., Dickson D.W., Boylan K.B., Graff-Radford N.R., Rademakers R. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72 (2): 245–256. DOI: 10.1016/j.neuron.2011.09.011.

Chen K.W., Chen J.A. Functional roles of long non-coding RNAs in motor neuron development and disease. J. Biomed. Sci. 2020; 27 (1): 38. DOI: 10.1186/s12929-020-00628-z.

Shaw P.J. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J. Neurol. Neurosurg. Psychiatry. 2005; 76 (8): 1046–1057. DOI: 10.1136/jnnp.2004.048652.

Shaw P.J., Forrest V., Ince P.G., Richardson J.P., Wastell H.J. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration. 1995; 4 (2): 209–216. DOI: 10.1006/neur.1995.0026.

Shaw P.J., Ince P.G., Falkous G., Mantle D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann. Neurol. 1995; 38 (4): 691–695. DOI: 10.1002/ana.410380424.

Manfredi G., Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005; 5 (2): 77–87. DOI: 10.1016/j.mito.2005.01.002.

Shi P., Gal J., Kwinter D.M., Liu X., Zhu H. Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim. Biophys. Acta. 2010; 1802 (1): 45–51. DOI: 10.1016/j.bbadis.2009.08.012.

Kodavati M., Wang H., Hegde M.L. Altered mitochondrial dynamics in motor neuron disease: An emerging perspective. Cells. 2020; 9 (4): 1065. DOI: 10.3390/cells9041065

De Vos K.J., Grierson A.J., Ackerley S., Miller C.C. Role of axonal transport in neurodegenerative diseases. Ann. Rev. Neurosci. 2008; 31: 151–173. DOI: 10.1146/annurev.neuro.31.061307.090711.

De Vos K.J., Chapman A.L., Tennant M.E., Manser C., Tudor E.L., Lau K.F., Brownlees J., Ackerley S., Shaw P.J., McLoughlin D.M., Shaw C.E., Leigh P.N., Miller C.C.J., Grierson A.J. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum. Mol. Genet. 2007; 16 (22): 27202728. DOI: 10.1093/hmg/ddm226.

Brownlees J., Ackerley S., Grierson A.J., Jacobsen N.J., Shea K., Anderton B.H., Leigh P.N., Shaw C.E., Miller C.C. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum. Mol. Genet. 2002; 11 (23): 2837–2844. DOI: 10.1093/hmg/11.23.2837.

Perrone Capano C., Pernas-Alonso R., di Porzio U. Neurofilament homeostasis and motoneurone degeneration. Bioessays. 2001; 23 (1): 24–33. DOI: 10.1002/1521-1878(200101)23:1<24::AID-BIES1004>3.0.CO;2-H.

Xu Z., Henderson R.D., David M., McCombe P.A. Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. PLoS One. 2016 ; 11 (10): e0164625. DOI: 10.1371/journal.pone.0164625.

Henkel J.S., Engelhardt J.I., Siklós L., Simpson E.P., Kim S.H., Pan T., Goodman J.C., Siddique T., Beers D.R., Appel S.H. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 2004; 55 (2): 221–235. DOI: 10.1002/ana.10805.

Siddique T., Deng H.X. Genetics of amyotrophic lateral sclerosis. Hum. Mol. Genet. 1996; 5: 1465–1470. DOI: 10.1093/hmg/5.supplement_1.1465.

Абрамычева Н.Ю., Лысогорская Е.В., Шпилюкова Ю.С., Ветчинова А.С., Захарова М.Н., Иллариошкин С.Н. Молекулярная структура бокового амиотрофического склероза в Российской популяции. Нервно-мышечные болезни. 2016; 6 (4): 21–27. DOI: 10.17650/2222-8721-2016-6-4-21-27.

Rosen D.R., Siddique T., Patterson D., Figlewicz D.A., Sapp P., Hentati A., Donaldson D., Goto J., O’Regan J.P., Deng H.X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993; 362 (6415): 59–62. DOI: 10.1038/362059a0.

Fahed A.C., McDonough B., Gouvion C.M., Newell K.L., Dure L.S., Bebin M., Bick A.G., Seidman J.G., Harter D.H., Seidman C.E. UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Ann. Neurol. 2014; 75 (5): 793–798. DOI: 10.1002/ana.24164.

Kunst C.B. Complex genetics of amyotrophic lateral sclerosis. Am. J. Hum. Genet. 2004; 75 (6): 933–947. DOI: 10.1086/426001.

Keller G.A., Warner T.G., Steimer K.S., Hallewell R.A. Cu,Zn superoxide dismutase is a peroxisomal enzyme in human fibroblasts and hepatoma cells. Proc. Natl. Acad. Sci. USA. 1991; 88 (16): 7381–7385. DOI: 10.1073/pnas.88.16.7381.

Andersen P.M., Nilsson P., Ala-Hurula V., Keränen M.L., Tarvainen I., Haltia T., Nilsson L., Binzer M., Forsgren L., Marklund S.L. Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. Nat. Genet. 1995; 10 (1): 61–66. DOI: 10.1038/ng0595-61.

Hand C.K., Mayeux-Portas V., Khoris J., Briolotti V., Clavelou P., Camu W., Rouleau G.A. Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family. Ann Neurol. 2001; 49 (2): 267–271. DOI: 10.1002/1531-8249(20010201)49:2<267::aidana51>3.0.co;2-d.

Al-Chalabi A., Andersen P.M., Chioza B., Shaw C., Sham P.C., Robberecht W., Matthijs G., Camu W., Marklund S.L., Forsgren L., Rouleau G., Laing N.G., Hurse P.V., Siddique T., Leigh P.N., Powell J.F. Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum. Mol. Genet. 1998; 7 (13): 2045–2050. DOI: 10.1093/hmg/7.13.2045.

Marangi G., Traynor B.J. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 2015; 1607: 75–93. DOI: 10.1016/j.brainres.2014.10.009.

Lysogorskaia E.V., Abramycheva N.Y., Zakharova M.N., Stepanova M.S., Moroz A.A., Rossokhin A.V., Illarioshkin S.N. Genetic studies of Russian patients with amyotrophic lateral sclerosis. Amyotroph. Lateral. Scler. Frontotemporal. Degener. 2015; 17 (1-2): 135–141. DOI: 10.3109/21678421.2015.1107100.

Yamashita S., Ando Y. Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis. Transl. Neurodegener. 2015; 4: 13. DOI: 10.1186/s40035-015-0036-y.

Lindberg M.J., Tibell L., Oliveberg M. Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state. Proc. Natl. Acad. Sci. USA. 2002; 99 (26): 16607–16612. DOI: 10.1073/pnas.262527099.

Лысогорская Е.В., Абрамычева Н.Ю., Захарова М.Н., Иллариошкин С.Н. Частота мутаций в гене SOD1 у российских пациентов с боковым амиотрофическим склерозом Медицинская генетика. 2013; 12 (4): 32–37. DOI: 10.1234/XXXX-XXXX-2013-4-32-37.

Deng H.X., Hentati A., Tainer J.A., Iqbal Z., Cayabyab A., Hung W.Y., Getzoff E.D., Hu P., Herzfeldt B., Roos R.P. et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 1993; 261 (5124): 1047–1051. DOI: 10.1126/science.8351519.

Cleveland D.W., Laing N., Hurse P.V., Brown R.H. Jr. Toxic mutants in Charcot’s sclerosis. Nature. 1995; 378 (6555): 342–343. DOI: 10.1038/378342a0.

Hayashi Y., Homma K., Ichijo H. SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS. Adv. Biol. Regul. 2016; 60: 95–104. DOI: 10.1016/j.jbior.2015.10.006.

Wiedau-Pazos M., Goto J.J., Rabizadeh S., Gralla E.B., Roe J.A., Lee M.K., Valentine J.S., Bredesen D.E. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science. 1996; 271 (5248): 515–518. DOI: 10.1126/science.271.5248.515.

Yim M.B., Kang J.H., Yim H.S., Kwak H.S., Chock P.B., Stadtman E.R. A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc. Natl. Acad. Sci. USA. 1996; 93 (12): 5709–5714. DOI: 10.1073/pnas.93.12.5709.

Van Landeghem G.F., Tabatabaie P., Beckman G., Beckman L., Andersen P.M. Manganese-containing superoxide dismutase signal sequence polymorphism associated with sporadic motor neuron disease. Eur. J. Neurol. 1999; 6 (6): 639–644. DOI: 10.1046/j.1468-1331.1999.660639.x.

Beckman J.S., Carson M., Smith C.D., Koppenol W.H. ALS, SOD and peroxynitrite. Nature. 1993; 364 (6438): 584. DOI: 10.1038/364584a0.

Wong P.C., Pardo C.A., Borchelt D.R., Lee M.K., Copeland N.G., Jenkins N.A., Sisodia S.S., Cleveland D.W., Price D.L. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995; 14 (6): 1105–1116. DOI: 10.1016/0896-6273(95)90259-7.

Kunst C.B., Mezey E., Brownstein M.J., Patterson D. Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat. Genet. 1997; 15 (1): 91–94. DOI: 10.1038/ng0197-91.

Shinder G.A., Lacourse M.C., Minotti S., Durham H.D. Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis. J. Biol. Chem. 2001; 276 (16): 12791–12796. DOI: 10.1074/jbc.M010759200.

Okado-Matsumoto A., Fridovich I. Amyotrophic lateral sclerosis: a proposed mechanism. Proc. Natl. Acad. Sci. USA. 2002; 99 (13): 9010–9014. DOI: 10.1073/pnas.132260399.

Ferri A., Gabbianelli R., Casciati A., Celsi F., Rotilio G., Carrì M.T. Oxidative inactivation of calcineurin by Cu,Zn superoxide dismutase G93A, a mutant typical of familial amyotrophic lateral sclerosis. J. Neurochem. 2001; 79 (3): 531–538. DOI: 10.1046/j.1471-4159.2001.00558.x.

Bruijn L.I., Houseweart M.K., Kato S., Anderson K.L., Anderson S.D., Ohama E., Reaume A.G., Scott R.W., Cleveland D.W. Aggregation and motor neuron toxicity of an ALSlinked SOD1 mutant independent from wild-type SOD1. Science. 1998; 281 (5384): 1851–1854. DOI: 10.1126/science.281.5384.1851.

Forsberg K., Graffmo K., Pakkenberg B., Weber M., Nielsen M., Marklund S., Brännström T., Andersen P.M. Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. J. Neurol. Neurosurg. Psychiatry. 2019; 90 (8): 861–869. DOI: 10.1136/jnnp-2018-319386.

Zinszner H., Sok J., Immanuel D., Yin Y., Ron D. TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J. Cell Sci. 1997; 110 ( 15): 1741–1750.

Ratti A., Buratti E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J. Neurochem. 2016; 138(1): 95–111. DOI: 10.1111/jnc.13625.

Lagier-Tourenne C., Polymenidou M., Hutt K.R., Vu A.Q., Baughn M., Huelga S.C., Clutario K.M., Ling S.C., Liang T.Y., Mazur C., Wancewicz E., Kim A.S., Watt A., Freier S., Hicks G.G., Donohue J.P., Shiue L., Bennett C.F., Ravits J., Cleveland D.W., Yeo G.W. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 2012; 15 (11): 1488–1497. DOI:10.1038/nn.3230.

Colombrita C., Onesto E., Buratti E., de la Grange P., Gumina V., Baralle F.E., Silani V., Ratti A. From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models. Biochim. Biophys. Acta. 2015; 1849 (12): 1398–1410. DOI: 10.1016/j.bbagrm.2015.10.015.

Lattante S., Rouleau G.A., Kabashi E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum. Mutat. 2013; 34 (6): 812–826. DOI: 10.1002/humu.22319.

Vance C., Scotter E.L., Nishimura A.L., Troakes C., Mitchell J.C., Kathe C., Urwin H., Manser C., Miller C.C., Hortobágyi T., Dragunow M., Rogelj B., Shaw C.E. ALS mutant FUS disrupts nuclear localization and sequesters wildtype FUS within cytoplasmic stress granules. Hum. Mol. Genet. 2013; 22 (13): 2676–2688. DOI: 10.1093/hmg/ddt117.

Nomura T., Watanabe S., Kaneko K., Yamanaka K., Nukina N., Furukawa Y. Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J. Biol. Chem. 2014; 289 (2): 1192–1202. DOI: 10.1074/jbc.M113.516492.

Kino Y., Washizu C., Kurosawa M., Yamada M., Miyazaki H., Akagi T., Hashikawa T., Doi H., Takumi T., Hicks G.G., Hattori N., Shimogori T., Nukina N. FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 2015; 3: 24. DOI: 10.1186/s40478-015-0202-6.

Mitchell J.C., McGoldrick P., Vance C., Hortobagyi T., Sreedharan J., Rogelj B., Tudor E.L., Smith B.N., Klasen C., Miller C.C., Cooper J.D., Greensmith L., Shaw C.E. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 2013; 125 (2): 273–288. DOI: 10.1007/s00401-012-1043-z.

Shelkovnikova T.A., Peters O.M., Deykin A.V., Connor-Robson N., Robinson H., Ustyugov A.A., Bachurin S.O.., Ermolkevich T.G., Goldman I.L., Sadchikova E.R., Kovrazhki na E.A., Skvortsova V.I., Ling S.C., Da Cruz S., Parone P.A., Buchman V.L., Ninkina N.N. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. J. Biol. Chem. 2013; 288 (35): 25266–25274. DOI: 10.1074/jbc.M113.492017.

Robinson H.K., Deykin A.V., Bronovitsky E.V., Ovchinnikov R.K., Ustyugov A.A., Shelkovnikova T.A., Kukharsky M.S., Ermolkevich T.G., Goldman I.L., Sadchikova E.R., Kovrazhkina E.A., Bachurin S.O., Buchman V.L., Ninkina N.N. Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif. Amyotroph. Lateral Scler. Frontotemporal. Degener. 2015; 16 (5-6): 402–409. DOI: 10.3109/21678421.2015.1040994.

Huang C., Zhou H., Tong J., Chen H., Liu Y.J., Wang D., Wei X., Xia X.G. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011; 7 (3): e1002011. DOI: 10.1371/journal.pgen.1002011.

Scekic-Zahirovic J., Sendscheid O., El Oussini H., Jambeau M., Sun Y., Mersmann S., Wagner M., Dieterlé S., Sinniger J., Dirrig-Grosch S., Drenner K., Birling M.C., Qiu J., Zhou Y., Li H., Fu X.D., Rouaux C., Shelkovnikova T., Witting A., Ludolph A.C., Kiefer F., Storkebaum E., Lagier-Tourenne C., Dupuis L. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J. 2016; 35 (10): 1077–1097. DOI: 10.15252/embj.201592559.

Sharma A., Lyashchenko A.K., Lu L., Nasrabady S.E., Elmaleh M., Mendelsohn M., Nemes A.., Tapia J.C., Mentis G.Z., Shneider N.A. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat. Commun. 2016; 7: 10465. DOI: 10.1038/ncomms10465.

Hennig S., Kong G., Mannen T., Sadowska A., Kobelke S., Blythe A., Knott G.J., Iyer K.S., Ho D., Newcombe E.A., Hosoki K., Goshima N., Kawaguchi T., Hatters D., TrinkleMulcahy L., Hirose T., Bond C.S., Fox A.H. Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles. J. Cell Biol. 2015; 210 (4): 529–539. DOI: 10.1083/jcb.201504117.

Zhou Y., Liu S., Liu G., Oztürk A., Hicks G.G. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013; 9 (10): e1003895. DOI: 10.1371/journal.pgen.1003895.

Qiu H., Lee S., Shang Y., Wang W.Y., Au K.F., Kamiya S., Barmada S.J., Finkbeiner S., Lui H., Carlton C.E., Tang A.A., Oldham M.C., Wang H., Shorter J., Filiano A.J., Roberson E.D., Tourtellotte W.G., Chen B., Tsai L.H., Huang E.J. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J. Clin. Invest. 2014; 124 (3): 981–999. DOI: 10.1172/JCI72723.

Ayala Y.M., Zago P., D’Ambrogio A., Xu Y.F., Petrucelli L., Buratti E., Baralle F.E. Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell Sci. 2008; 121 (22): 3778–3785. DOI: 10.1242/jcs.038950.

Buratti E., Baralle F.E. The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biol. 2010; 7 (4): 420–429. DOI: 10.4161/rna.7.4.12205.

Tollervey J.R., Curk T., Rogelj B., Briese M., Cereda M., Kayikci M., König J., Hortobágyi T., Nishimura A.L., Zupunski V., Patani R., Chandran S., Rot G., Zupan B., Shaw C.E., Ule J. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 2011; 14 (4): 452–458. DOI: 10.1038/nn.2778.

Leigh P.N., Whitwell H., Garofalo O., Buller J., Swash M., Martin J.E., Gallo J.M., Weller R.O., Anderton B.H. Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain. 1991; 114 (2): 775–788. DOI: 10.1093/brain/114.2.775.

Arai T., Hasegawa M., Akiyama H., Ikeda K., Nonaka T., Mori H., Mann D., Tsuchiya K., Yoshida M., Hashizume Y., Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 2006; 351 (3): 602–611. DOI: 10.1016/j.bbrc.2006.10.093.

Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micsenyi M.C., Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M., McCluskey L.F., Miller B.L., Masliah E., Mackenzie I.R., Feldman H., Feiden W., Kretzschmar H.A., Trojanowski J.Q., Lee V.M. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314 (5796): 130–133. DOI: 10.1126/science.1134108.

Giordana M.T., Piccinini M., Grifoni S., De Marco G., Vercellino M., Magistrello M., Pellerino A., Buccinnà B., Lupino E., Rinaudo M.T. TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol. 2010; 20 (2): 351–360. DOI: 10.1111/j.1750-3639.2009.00284.x.

Schipper L.J., Raaphorst J., Aronica E., Baas F., de Haan R., de Visser M., Troost D. Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review. Neuropathol. Appl. Neurobiol. 2016; 42 (6): 547–560. DOI: 10.1111/nan.12284.

Buratti E., Brindisi A., Giombi M., Tisminetzky S., Ayala Y.M., Baralle F.E. TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J. Biol. Chem. 2005; 280 (45): 37572–37584. DOI: 10.1074/jbc.M505557200.

Kraemer B.C., Schuck T., Wheeler J.M., Robinson L.C., Trojanowski J.Q., Lee V.M., Schellenberg G.D. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 2010; 119 (4): 409–419. DOI: 10.1007/s00401-010-0659-0.

Chiang P.M., Ling J., Jeong Y.H., Price D.L., Aja S.M., Wong P.C. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc. Natl. Acad. Sci. USA. 2010; 107 (37): 16320–16324. DOI: 10.1073/pnas.1002176107.

Ash P.E., Zhang Y.J., Roberts C.M., Saldi T., Hutter H., Buratti E., Petrucelli L., Link C.D. Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum. Mol. Genet. 2010; 19 (16): 3206–3218. DOI:10.1093/hmg/ddq230.

Kabashi E., Lin L., Tradewell M.L., Dion P.A., Bercier V., Bourgouin P., Rochefort D., Bel Hadj S., Durham H.D., Vande Velde C., Rouleau G.A., Drapeau P. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 2010; 19 (4): 671–683. DOI: 10.1093/hmg/ddp534.

Xu Y.F., Zhang Y.J., Lin W.L., Cao X., Stetler C., Dickson D.W., Lewis J., Petrucelli L. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol. Neurodegener. 2011; 6: 73. DOI: 10.1186/1750-1326-6-73.

Koyama A., Sugai A., Kato T., Ishihara T., Shiga A., Toyoshima Y., Koyama M., Konno T., Hirokawa S., Yokoseki A., Nishizawa M., Kakita A., Takahashi H., Onodera O. Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. Nucleic. Acids Res. 2016; 44 (12): 5820–5836. DOI: 10.1093/nar/gkw499.

Highley J.R., Kirby J., Jansweijer J.A., Webb P.S., Hewamadduma C.A., Heath P.R., Higginbottom A., Raman R., Ferraiuolo L., Cooper-Knock J., McDermott C.J., Wharton S.B., Shaw P.J., Ince P.G. Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones. Neuropathol. Appl. Neurobiol. 2014; 40 (6): 670–685. DOI: 10.1111/nan.12148.

Klim J.R., Williams L.A., Limone F., Guerra San Juan I., Davis-Dusenbery B.N., Mordes D.A., Burberry A., Steinbaugh M.J., Gamage K.K., Kirchner R., Moccia R., Cassel S.H., Chen K., Wainger B.J., Woolf C.J., Eggan K. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat. Neurosci. 2019; 22 (2): 167–179. DOI: 10.1038/s41593-018-0300-4.

Buratti E. TDP-43 post-translational modifications in health and disease. Expert. Opin. Ther. Targets. 2018; 22 (3): 279–293. DOI: 10.1080/14728222.2018.1439923.

Farg M.A., Sundaramoorthy V., Sultana J.M., Yang S., Atkinson R.A., Levina V., Halloran M.A., Gleeson P.A., Blair I.P., Soo K.Y., King A.E., Atkin J.D. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum. Mol. Genet. 2014; 23 (13): 3579–3595. DOI: 10.1093/hmg/ddu068.

Waite A.J., Bäumer D., East S., Neal J., Morris H.R., Ansorge O., Blake D.J. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol. Aging. 2014; 35 (7): 1779.e5–1779.e13. DOI: 10.1016/j.neurobiolaging.2014.01.016.

Koppers M., Blokhuis A.M., Westeneng H.J., Terpstra M.L., Zundel C.A., Vieira de Sá R., Schellevis R.D., Waite A.J., Blake D.J., Veldink J.H., van den Berg L.H., Pasterkamp R.J. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 2015; 78 (3): 426–438. DOI: 10.1002/ana.24453.

Sareen D., O’Rourke J.G., Meera P., Muhammad A.K., Grant S., Simpkinson M., Bell S., Carmona S., Ornelas L., Sahabian A., Gendron T., Petrucelli L., Baughn M., Ravits J., Harms M.B., Rigo F., Bennett C.F., Otis T.S., Svendsen C.N., Baloh R.H. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 2013; 5 (208): 208ra149. DOI: 10.1126/scitranslmed.3007529.

Barker H.V., Niblock M., Lee Y.B., Shaw C.E., Gallo J.M. RNA misprocessing in C9orf72-Linked neurodegeneration. Front. Cell Neurosci. 2017; 11: 195. DOI: 10.3389/fncel.2017.00195.

Ash P.E., Bieniek K.F., Gendron T.F., Caulfield T., Lin W.L., Dejesus-Hernandez M., van Blitterswijk M.M., JansenWest K., Paul J.W., Rademakers R., Boylan K.B., Dickson D.W., Petrucelli L. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013; 77 (4): 639–646. DOI: 10.1016/j.neuron.2013.02.004.

Todd T.W., Petrucelli L. Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions. J. Neurochem. 2016; 138(1): 145–162. DOI: 10.1111/jnc.13623.

Fratta P., Mizielinska S., Nicoll A.J., Zloh M., Fisher E.M., Parkinson G., Isaacs A.M. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2012; 2: 1016. DOI: 10.1038/srep01016.

The authors declare that there are no conflicts of interest present.