The Fragile X Protein Family in Amyotrophic Lateral Sclerosis.
Amyotrophic lateral sclerosis ALS
FMR1 FMRP
FXR1 FXR1P
FXR2 FXR2P
Neurodegenerative disease
Protein aggregation
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
29
11
2022
accepted:
23
03
2023
medline:
29
5
2023
pubmed:
30
3
2023
entrez:
29
3
2023
Statut:
ppublish
Résumé
The fragile X protein (FXP) family comprises the multifunctional RNA-binding proteins FMR1, FXR1, and FXR2 that play an important role in RNA metabolism and regulation of translation, but also in DNA damage and cellular stress responses, mitochondrial organization, and more. FMR1 is well known for its implication in neurodevelopmental diseases. Recent evidence suggests substantial contribution of this protein family to amyotrophic lateral sclerosis (ALS) pathogenesis. ALS is a highly heterogeneous neurodegenerative disease with multiple genetic and unclear environmental causes and very limited treatment options. The loss of motoneurons in ALS is still poorly understood, especially because pathogenic mechanisms are often restricted to patients with mutations in specific causative genes. Identification of converging disease mechanisms evident in most patients and suitable for therapeutic intervention is therefore of high importance. Recently, deregulation of the FXPs has been linked to pathogenic processes in different types of ALS. Strikingly, in many cases, available data points towards loss of expression and/or function of the FXPs early in the disease, or even at the presymptomatic state. In this review, we briefly introduce the FXPs and summarize available data about these proteins in ALS. This includes their relation to TDP-43, FUS, and ALS-related miRNAs, as well as their possible contribution to pathogenic protein aggregation and defective RNA editing. Furthermore, open questions that need to be addressed before definitively judging suitability of these proteins as novel therapeutic targets are discussed.
Identifiants
pubmed: 36991279
doi: 10.1007/s12035-023-03330-x
pii: 10.1007/s12035-023-03330-x
pmc: PMC10224833
doi:
Substances chimiques
RNA-Binding Proteins
0
RNA-Binding Protein FUS
0
FXR1 protein, human
0
FMR1 protein, human
0
Fragile X Mental Retardation Protein
139135-51-6
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
3898-3910Informations de copyright
© 2023. The Author(s).
Références
Hardiman O, Al-Chalabi A, Chio A et al (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3:17071. https://doi.org/10.1038/nrdp.2017.71
doi: 10.1038/nrdp.2017.71
pubmed: 28980624
Brown RH, Al-Chalabi A (2017) Amyotrophic lateral sclerosis. N Engl J Med 377:162–172. https://doi.org/10.1056/NEJMra1603471
doi: 10.1056/NEJMra1603471
pubmed: 28700839
Majumder M, Johnson RH, Palanisamy V (2020) Fragile X-related protein family: a double-edged sword in neurodevelopmental disorders and cancer. Crit Rev Biochem Mol Biol 55:409–424. https://doi.org/10.1080/10409238.2020.1810621
doi: 10.1080/10409238.2020.1810621
pubmed: 32878499
pmcid: 7695039
Richter JD, Zhao X (2021) The molecular biology of FMRP: new Insights into Fragile X Syndrome. Nat Rev Neurosci 22:209–222. https://doi.org/10.1038/s41583-021-00432-0
doi: 10.1038/s41583-021-00432-0
pubmed: 33608673
pmcid: 8094212
Chen C, Nott TJ, Jin J, Pawson T (2011) Deciphering arginine methylation: Tudor tells the tale. Nat Rev Mol Cell Biol 12:629–642. https://doi.org/10.1038/nrm3185
doi: 10.1038/nrm3185
pubmed: 21915143
Freischmidt A, Goswami A, Limm K et al (2021) A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis. Brain J Neurol 144:1214–1229. https://doi.org/10.1093/brain/awab018
doi: 10.1093/brain/awab018
Blokhuis AM, Koppers M, Groen EJN et al (2016) Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways. Acta Neuropathol (Berl) 132:175–196. https://doi.org/10.1007/s00401-016-1575-8
doi: 10.1007/s00401-016-1575-8
pubmed: 27164932
He Q, Ge W (2017) The tandem Agenet domain of fragile X mental retardation protein interacts with FUS. Sci Rep 7:962. https://doi.org/10.1038/s41598-017-01175-8
doi: 10.1038/s41598-017-01175-8
pubmed: 28424484
pmcid: 5430443
Dormann D, Madl T, Valori CF et al (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J 31:4258–4275. https://doi.org/10.1038/emboj.2012.261
doi: 10.1038/emboj.2012.261
pubmed: 22968170
pmcid: 3501225
Blum M, Chang H-Y, Chuguransky S et al (2021) The InterPro protein families and domains database: 20 years on. Nucleic Acids Res 49:D344–D354. https://doi.org/10.1093/nar/gkaa977
doi: 10.1093/nar/gkaa977
pubmed: 33156333
Uhlén M, Fagerberg L, Hallström BM et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. https://doi.org/10.1126/science.1260419
doi: 10.1126/science.1260419
pubmed: 25613900
Banerjee A, Ifrim MF, Valdez AN et al (2018) Aberrant RNA translation in fragile X syndrome: from FMRP mechanisms to emerging therapeutic strategies. Brain Res 1693:24–36. https://doi.org/10.1016/j.brainres.2018.04.008
doi: 10.1016/j.brainres.2018.04.008
pubmed: 29653083
pmcid: 7377270
Guo Y, Chen X, Xing R et al (2018) Interplay between FMRP and lncRNA TUG1 regulates axonal development through mediating SnoN-Ccd1 pathway. Hum Mol Genet 27:475–485. https://doi.org/10.1093/hmg/ddx417
doi: 10.1093/hmg/ddx417
pubmed: 29211876
Taha MS, Haghighi F, Stefanski A et al (2021) Novel FMRP interaction networks linked to cellular stress. FEBS J 288:837–860. https://doi.org/10.1111/febs.15443
doi: 10.1111/febs.15443
pubmed: 32525608
Deng P-Y, Klyachko VA (2021) Channelopathies in fragile X syndrome. Nat Rev Neurosci 22:275–289. https://doi.org/10.1038/s41583-021-00445-9
doi: 10.1038/s41583-021-00445-9
pubmed: 33828309
pmcid: 8863066
Glauninger H, Wong Hickernell CJ, Bard JAM, Drummond DA (2022) Stressful steps: progress and challenges in understanding stress-induced mRNA condensation and accumulation in stress granules. Mol Cell 82:2544–2556. https://doi.org/10.1016/j.molcel.2022.05.014
doi: 10.1016/j.molcel.2022.05.014
pubmed: 35662398
Jain S, Wheeler JR, Walters RW et al (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487–498. https://doi.org/10.1016/j.cell.2015.12.038
doi: 10.1016/j.cell.2015.12.038
pubmed: 26777405
pmcid: 4733397
Mazroui R, Huot M-E, Tremblay S et al (2002) Trapping of messenger RNA by fragile X mental retardation protein into cytoplasmic granules induces translation repression. Hum Mol Genet 11:3007–3017. https://doi.org/10.1093/hmg/11.24.3007
doi: 10.1093/hmg/11.24.3007
pubmed: 12417522
Didiot M-C, Subramanian M, Flatter E et al (2009) Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly. Mol Biol Cell 20:428–437. https://doi.org/10.1091/mbc.E08-07-0737
doi: 10.1091/mbc.E08-07-0737
pubmed: 19005212
pmcid: 2613094
Jeon SJ, Han S-H, Yang S-I et al (2012) Positive feedback regulation of Akt-FMRP pathway protects neurons from cell death. J Neurochem 123:226–238. https://doi.org/10.1111/j.1471-4159.2012.07886.x
doi: 10.1111/j.1471-4159.2012.07886.x
pubmed: 22817682
Jeon SJ, Seo JE, Yang S-I et al (2011) Cellular stress-induced up-regulation of FMRP promotes cell survival by modulating PI3K-Akt phosphorylation cascades. J Biomed Sci 18:17. https://doi.org/10.1186/1423-0127-18-17
doi: 10.1186/1423-0127-18-17
pubmed: 21314987
pmcid: 3045291
Hornbeck PV, Zhang B, Murray B et al (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 43:D512–D520. https://doi.org/10.1093/nar/gku1267
doi: 10.1093/nar/gku1267
pubmed: 25514926
Prieto M, Folci A, Martin S (2020) Post-translational modifications of the fragile X mental retardation protein in neuronal function and dysfunction. Mol Psychiatry 25:1688–1703. https://doi.org/10.1038/s41380-019-0629-4
doi: 10.1038/s41380-019-0629-4
pubmed: 31822816
Say E, Tay H-G, Zhao Z et al (2010) A functional requirement for PAK1 binding to the KH(2) domain of the fragile X protein-related FXR1. Mol Cell 38:236–249. https://doi.org/10.1016/j.molcel.2010.04.004
doi: 10.1016/j.molcel.2010.04.004
pubmed: 20417602
Hagerman RJ, Berry-Kravis E, Hazlett HC et al (2017) Fragile X syndrome. Nat Rev Dis Primers 3:17065. https://doi.org/10.1038/nrdp.2017.65
doi: 10.1038/nrdp.2017.65
pubmed: 28960184
Rosario R, Anderson R (2020) The molecular mechanisms that underlie fragile X-associated premature ovarian insufficiency: is it RNA or protein based? Mol Hum Reprod 26:727–737. https://doi.org/10.1093/molehr/gaaa057
doi: 10.1093/molehr/gaaa057
pubmed: 32777047
pmcid: 7566375
Liufu T, Zheng Y, Yu J et al (2022) The polyG diseases: a new disease entity. Acta Neuropathol Commun 10:79. https://doi.org/10.1186/s40478-022-01383-y
doi: 10.1186/s40478-022-01383-y
pubmed: 35642014
pmcid: 9153130
Aishworiya R, Protic D, Hagerman R (2022) Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications. J Neurol 269:4676–4683. https://doi.org/10.1007/s00415-022-11209-5
doi: 10.1007/s00415-022-11209-5
pubmed: 35723724
Estañ MC, Fernández-Núñez E, Zaki MS et al (2019) Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. Nat Commun 10:797. https://doi.org/10.1038/s41467-019-08548-9
doi: 10.1038/s41467-019-08548-9
pubmed: 30770808
pmcid: 6377633
Bampton A, Gittings LM, Fratta P et al (2020) The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 140:599–623. https://doi.org/10.1007/s00401-020-02203-0
doi: 10.1007/s00401-020-02203-0
pubmed: 32748079
Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. https://doi.org/10.1038/ng.132
doi: 10.1038/ng.132
pubmed: 18372902
Al-Chalabi A, Jones A, Troakes C et al (2012) The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 124:339–352. https://doi.org/10.1007/s00401-012-1022-4
doi: 10.1007/s00401-012-1022-4
pubmed: 22903397
Ikenaka K, Ishigaki S, Iguchi Y et al (2020) Characteristic features of FUS inclusions in spinal motor neurons of sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 79:370–377. https://doi.org/10.1093/jnen/nlaa003
doi: 10.1093/jnen/nlaa003
pubmed: 32142134
Tyzack GE, Luisier R, Taha DM et al (2019) Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. Brain J Neurol 142:2572–2580. https://doi.org/10.1093/brain/awz217
doi: 10.1093/brain/awz217
Nolan M, Talbot K, Ansorge O (2016) Pathogenesis of FUS-associated ALS and FTD: insights from rodent models. Acta Neuropathol Commun 4:99. https://doi.org/10.1186/s40478-016-0358-8
doi: 10.1186/s40478-016-0358-8
pubmed: 27600654
pmcid: 5011941
Wang I-F, Wu L-S, Chang H-Y, Shen C-KJ (2008) TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem 105:797–806. https://doi.org/10.1111/j.1471-4159.2007.05190.x
doi: 10.1111/j.1471-4159.2007.05190.x
pubmed: 18088371
Yu Z, Fan D, Gui B et al (2012) Neurodegeneration-associated TDP-43 interacts with fragile X mental retardation protein (FMRP)/Staufen (STAU1) and regulates SIRT1 expression in neuronal cells. J Biol Chem 287:22560–22572. https://doi.org/10.1074/jbc.M112.357582
doi: 10.1074/jbc.M112.357582
pubmed: 22584570
pmcid: 3391095
Chu J-F, Majumder P, Chatterjee B et al (2019) TDP-43 Regulates coupled dendritic mRNA transport-translation processes in co-operation with FMRP and Staufen1. Cell Rep 29:3118–3133.e6. https://doi.org/10.1016/j.celrep.2019.10.061
doi: 10.1016/j.celrep.2019.10.061
pubmed: 31801077
Majumder P, Chu J-F, Chatterjee B et al (2016) Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP. Acta Neuropathol (Berl) 132:721–738. https://doi.org/10.1007/s00401-016-1603-8
doi: 10.1007/s00401-016-1603-8
pubmed: 27518042
Ferro D, Yao S, Zarnescu DC (2018) Dynamic duo - FMRP and TDP-43: Regulating common targets, causing different diseases. Brain Res 1693:37–42. https://doi.org/10.1016/j.brainres.2018.04.034
doi: 10.1016/j.brainres.2018.04.034
pubmed: 29715444
pmcid: 5997554
Coyne AN, Yamada SB, Siddegowda BB et al (2015) Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum Mol Genet 24:6886–6898. https://doi.org/10.1093/hmg/ddv389
doi: 10.1093/hmg/ddv389
pubmed: 26385636
pmcid: 5007633
El Fatimy R, Davidovic L, Tremblay S et al (2016) Tracking the fragile X mental retardation protein in a highly ordered neuronal ribonucleoparticles population: a link between stalled polyribosomes and RNA granules. PLoS Genet 12:e1006192. https://doi.org/10.1371/journal.pgen.1006192
doi: 10.1371/journal.pgen.1006192
pubmed: 27462983
pmcid: 4963131
Birsa N, Ule AM, Garone MG et al (2021) FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Sci Adv 7:eabf8660. https://doi.org/10.1126/sciadv.abf8660
doi: 10.1126/sciadv.abf8660
pubmed: 34290090
pmcid: 8294762
Andersson MK, Ståhlberg A, Arvidsson Y et al (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37. https://doi.org/10.1186/1471-2121-9-37
doi: 10.1186/1471-2121-9-37
pubmed: 18620564
pmcid: 2478660
Kamelgarn M, Chen J, Kuang L et al (2018) ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay. Proc Natl Acad Sci U S A 115:E11904–E11913. https://doi.org/10.1073/pnas.1810413115
doi: 10.1073/pnas.1810413115
pubmed: 30455313
pmcid: 6304956
Murakami T, Qamar S, Lin JQ et al (2015) ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88:678–690. https://doi.org/10.1016/j.neuron.2015.10.030
doi: 10.1016/j.neuron.2015.10.030
pubmed: 26526393
pmcid: 4660210
Sévigny M, Bourdeau Julien I, Venkatasubramani JP et al (2020) FUS contributes to mTOR-dependent inhibition of translation. J Biol Chem 295:18459–18473. https://doi.org/10.1074/jbc.RA120.013801
doi: 10.1074/jbc.RA120.013801
pubmed: 33082139
Yasuda K, Zhang H, Loiselle D et al (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203:737–746. https://doi.org/10.1083/jcb.201306058
doi: 10.1083/jcb.201306058
pubmed: 24297750
pmcid: 3857475
Garone MG, Birsa N, Rosito M et al (2021) ALS-related FUS mutations alter axon growth in motoneurons and affect HuD/ELAVL4 and FMRP activity. Commun Biol 4:1025. https://doi.org/10.1038/s42003-021-02538-8
doi: 10.1038/s42003-021-02538-8
pubmed: 34471224
pmcid: 8410767
Chen Y, Cohen TJ (2019) Aggregation of the nucleic acid-binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation. J Biol Chem 294:3696–3706. https://doi.org/10.1074/jbc.RA118.006351
doi: 10.1074/jbc.RA118.006351
pubmed: 30630951
pmcid: 6416430
Wiesner D, Tar L, Linkus B et al (2018) Reversible induction of TDP-43 granules in cortical neurons after traumatic injury. Exp Neurol 299:15–25. https://doi.org/10.1016/j.expneurol.2017.09.011
doi: 10.1016/j.expneurol.2017.09.011
pubmed: 28941811
Agote-Aran A, Schmucker S, Jerabkova K et al (2020) Spatial control of nucleoporin condensation by fragile X-related proteins. EMBO J 39:e104467. https://doi.org/10.15252/embj.2020104467
doi: 10.15252/embj.2020104467
pubmed: 32706158
pmcid: 7560220
Chou C-C, Zhang Y, Umoh ME et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21:228–239. https://doi.org/10.1038/s41593-017-0047-3
doi: 10.1038/s41593-017-0047-3
pubmed: 29311743
pmcid: 5800968
Gleixner AM, Verdone BM, Otte CG et al (2022) NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility. Nat Commun 13:3380. https://doi.org/10.1038/s41467-022-31098-6
doi: 10.1038/s41467-022-31098-6
pubmed: 35697676
pmcid: 9192689
Coyne AN, Baskerville V, Zaepfel BL et al (2021) Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Sci Transl Med 13:eabe1923. https://doi.org/10.1126/scitranslmed.abe1923
doi: 10.1126/scitranslmed.abe1923
pubmed: 34321318
pmcid: 9022198
Bartel DP (2018) Metazoan MicroRNAs. Cell 173:20–51. https://doi.org/10.1016/j.cell.2018.03.006
doi: 10.1016/j.cell.2018.03.006
pubmed: 29570994
pmcid: 6091663
Buratti E, De Conti L, Stuani C, et al (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J 277:2268–2281. https://doi.org/10.1111/j.1742-4658.2010.07643.x
Kawahara Y, Mieda-Sato A (2012) TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci U S A 109:3347–3352. https://doi.org/10.1073/pnas.1112427109
doi: 10.1073/pnas.1112427109
pubmed: 22323604
pmcid: 3295278
Morlando M, Dini Modigliani S, Torrelli G et al (2012) FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J 31:4502–4510. https://doi.org/10.1038/emboj.2012.319
doi: 10.1038/emboj.2012.319
pubmed: 23232809
pmcid: 3545295
Guil S, Cáceres JF (2007) The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol 14:591–596. https://doi.org/10.1038/nsmb1250
doi: 10.1038/nsmb1250
pubmed: 17558416
Treiber T, Treiber N, Plessmann U et al (2017) A compendium of RNA-binding proteins that regulate MicroRNA biogenesis. Mol Cell 66:270–284.e13. https://doi.org/10.1016/j.molcel.2017.03.014
doi: 10.1016/j.molcel.2017.03.014
pubmed: 28431233
Emde A, Eitan C, Liou L-L et al (2015) Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS. EMBO J 34:2633–2651. https://doi.org/10.15252/embj.201490493
doi: 10.15252/embj.201490493
pubmed: 26330466
pmcid: 4641530
Haramati S, Chapnik E, Sztainberg Y et al (2010) miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 107:13111–13116. https://doi.org/10.1073/pnas.1006151107
doi: 10.1073/pnas.1006151107
pubmed: 20616011
pmcid: 2919953
Freischmidt A, Müller K, Zondler L et al (2014) Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers. Brain J Neurol 137:2938–2950. https://doi.org/10.1093/brain/awu249
doi: 10.1093/brain/awu249
Freischmidt A, Müller K, Zondler L et al (2015) Serum microRNAs in sporadic amyotrophic lateral sclerosis. Neurobiol Aging 36:2660.e15–2660.e20. https://doi.org/10.1016/j.neurobiolaging.2015.06.003
doi: 10.1016/j.neurobiolaging.2015.06.003
pubmed: 26142125
Sommer B, Köhler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67:11–19. https://doi.org/10.1016/0092-8674(91)90568-j
doi: 10.1016/0092-8674(91)90568-j
pubmed: 1717158
Kawahara Y, Ito K, Sun H et al (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427:801. https://doi.org/10.1038/427801a
doi: 10.1038/427801a
pubmed: 14985749
Hosaka T, Tsuji H, Kwak S (2021) RNA editing: a new therapeutic target in amyotrophic lateral sclerosis and other neurological diseases. Int J Mol Sci 22:10958. https://doi.org/10.3390/ijms222010958
doi: 10.3390/ijms222010958
pubmed: 34681616
pmcid: 8536083
Moore S, Alsop E, Lorenzini I et al (2019) ADAR2 Mislocalization and widespread RNA editing aberrations in C9orf72-Mediated ALS/FTD. Acta Neuropathol (Berl) 138:49–65. https://doi.org/10.1007/s00401-019-01999-w
doi: 10.1007/s00401-019-01999-w
pubmed: 30945056
Bhogal B, Jepson JE, Savva YA et al (2011) Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat Neurosci 14:1517–1524. https://doi.org/10.1038/nn.2950
doi: 10.1038/nn.2950
pubmed: 22037499
pmcid: 3225737
Shamay-Ramot A, Khermesh K, Porath HT, et al (2015) Fmrp interacts with adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish. PLoS Genet 11:e1005702. https://doi.org/10.1371/journal.pgen.1005702
Filippini A, Bonini D, Lacoux C et al (2017) Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse. RNA Biol 14:1580–1591. https://doi.org/10.1080/15476286.2017.1338232
doi: 10.1080/15476286.2017.1338232
pubmed: 28640668
pmcid: 5785225
Tran SS, Jun H-I, Bahn JH et al (2019) Widespread RNA editing dysregulation in brains from autistic individuals. Nat Neurosci 22:25–36. https://doi.org/10.1038/s41593-018-0287-x
doi: 10.1038/s41593-018-0287-x
pubmed: 30559470
La Via L, Bonini D, Russo I et al (2013) Modulation of dendritic AMPA receptor mRNA trafficking by RNA splicing and editing. Nucleic Acids Res 41:617–631. https://doi.org/10.1093/nar/gks1223
doi: 10.1093/nar/gks1223
pubmed: 23166306
Salpietro V, Dixon CL, Guo H et al (2019) AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nat Commun 10:3094. https://doi.org/10.1038/s41467-019-10910-w
doi: 10.1038/s41467-019-10910-w
pubmed: 31300657
pmcid: 6626132
Elden AC, Kim H-J, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. https://doi.org/10.1038/nature09320
doi: 10.1038/nature09320
pubmed: 20740007
pmcid: 2965417
Laffita-Mesa JM, Paucar M, Svenningsson P (2021) Ataxin-2 gene: a powerful modulator of neurological disorders. Curr Opin Neurol 34:578–588. https://doi.org/10.1097/WCO.0000000000000959
doi: 10.1097/WCO.0000000000000959
pubmed: 34010218
pmcid: 8279897
Freischmidt A, Wieland T, Richter B et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18:631–636. https://doi.org/10.1038/nn.4000
doi: 10.1038/nn.4000
pubmed: 25803835
Li S, Wang L, Berman M et al (2011) Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35:426–440. https://doi.org/10.1016/j.immuni.2011.06.014
doi: 10.1016/j.immuni.2011.06.014
pubmed: 21903422
pmcid: 3253658
Bechara EG, Didiot MC, Melko M et al (2009) A novel function for fragile X mental retardation protein in translational activation. PLoS Biol 7:e16. https://doi.org/10.1371/journal.pbio.1000016
doi: 10.1371/journal.pbio.1000016
pubmed: 19166269
Casañas JJ, Montesinos ML (2022) Proteomic characterization of spinal cord synaptoneurosomes from Tg-SOD1/G93A mice supports a role for MNK1 and local translation in the early stages of amyotrophic lateral sclerosis. Mol Cell Neurosci 103792. https://doi.org/10.1016/j.mcn.2022.103792
Almeida S, Gascon E, Tran H et al (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol (Berl) 126:385–399. https://doi.org/10.1007/s00401-013-1149-y
doi: 10.1007/s00401-013-1149-y
pubmed: 23836290
Donnelly CJ, Zhang P-W, Pham JT et al (2013) RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron 80:415–428. https://doi.org/10.1016/j.neuron.2013.10.015
doi: 10.1016/j.neuron.2013.10.015
pubmed: 24139042
pmcid: 4098943
Haeusler AR, Donnelly CJ, Periz G et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195–200. https://doi.org/10.1038/nature13124
doi: 10.1038/nature13124
pubmed: 24598541
pmcid: 4046618
Rossi S, Serrano A, Gerbino V et al (2015) Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J Cell Sci 128:1787–1799. https://doi.org/10.1242/jcs.165332
doi: 10.1242/jcs.165332
pubmed: 25788698
Burguete AS, Almeida S, Gao F-B, et al (2015) GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4:e08881. https://doi.org/10.7554/eLife.08881
Luo Y, Hitz BC, Gabdank I et al (2020) New developments on the Encyclopedia of DNA Elements (ENCODE) data portal. Nucleic Acids Res 48:D882–D889. https://doi.org/10.1093/nar/gkz1062
doi: 10.1093/nar/gkz1062
pubmed: 31713622
Van Nostrand EL, Pratt GA, Shishkin AA et al (2016) Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat Methods 13:508–514. https://doi.org/10.1038/nmeth.3810
doi: 10.1038/nmeth.3810
pubmed: 27018577
pmcid: 4887338
Kanehisa M, Furumichi M, Sato Y et al (2022) KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res gkac963. https://doi.org/10.1093/nar/gkac963
Abel O, Powell JF, Andersen PM, Al-Chalabi A (2012) ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat 33:1345–1351. https://doi.org/10.1002/humu.22157
doi: 10.1002/humu.22157
pubmed: 22753137
Lill CM, Abel O, Bertram L, Al-Chalabi A (2011) Keeping up with genetic discoveries in amyotrophic lateral sclerosis: The ALSoD and ALSGene databases. Amyotroph Lateral Scler 12:238–249. https://doi.org/10.3109/17482968.2011.584629
doi: 10.3109/17482968.2011.584629
pubmed: 21702733
Xie Z, Bailey A, Kuleshov MV et al (2021) Gene Set Knowledge Discovery with Enrichr. Curr Protoc 1:e90. https://doi.org/10.1002/cpz1.90
doi: 10.1002/cpz1.90
pubmed: 33780170
pmcid: 8152575
Bleuzé L, Triaca V, Borreca A (2021) FMRP-Driven neuropathology in autistic spectrum disorder and alzheimer’s disease: a losing game. Front Mol Biosci 8:699613. https://doi.org/10.3389/fmolb.2021.699613
Borreca A, Gironi K, Amadoro G, Ammassari-Teule M (2016) Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease. Mol Neurobiol 53:3227–3234. https://doi.org/10.1007/s12035-015-9229-8
doi: 10.1007/s12035-015-9229-8
pubmed: 26048669
Tan Y, Sgobio C, Arzberger T et al (2020) Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson’s disease. Acta Neuropathol (Berl) 139:319–345. https://doi.org/10.1007/s00401-019-02099-5
doi: 10.1007/s00401-019-02099-5
pubmed: 31768670
Ruf WP, Freischmidt A, Grozdanov V et al (2021) Protein Binding Partners of Dysregulated miRNAs in Parkinson’s Disease Serum. Cells 10:791. https://doi.org/10.3390/cells10040791
doi: 10.3390/cells10040791
pubmed: 33918274
pmcid: 8065836
van Rheenen W, van der Spek RAA, Bakker MK et al (2021) Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet 53:1636–1648. https://doi.org/10.1038/s41588-021-00973-1
doi: 10.1038/s41588-021-00973-1
pubmed: 34873335
pmcid: 8648564
Al-Chalabi A, Calvo A, Chio A et al (2014) Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol 13:1108–1113. https://doi.org/10.1016/S1474-4422(14)70219-4
doi: 10.1016/S1474-4422(14)70219-4
pubmed: 25300936
pmcid: 4197338
Chiò A, Mazzini L, D’Alfonso S et al (2018) The multistep hypothesis of ALS revisited: The role of genetic mutations. Neurology 91:e635–e642. https://doi.org/10.1212/WNL.0000000000005996
doi: 10.1212/WNL.0000000000005996
pubmed: 30045958
pmcid: 6105040