Abstract
Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2–3 years. These expansion disorders have substantial overlap** clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases — similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.
Key points
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Pathogenic non-coding CGG repeat expansions in different genes cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy and oculopharyngodistal myopathy, respectively.
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CGG repeat expansion disorders have overlap** clinical, MRI and histopathological features, including parkinsonism, ataxia, dementia, autonomic dysfunctions, myopathy, ubiquitin-positive inclusion bodies, middle cerebellar peduncle hyperintensity and leukoencephalopathy.
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RNA toxicity, disturbance of membraneless organelle function, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment are likely molecular mechanisms.
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Development of novel disease models, single-cell expression profiling and greater understanding of pathophysiological mechanisms and the effects of various repeat lengths and repeat interruptions could facilitate the development of therapeutic approaches.
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Short antisense oligonucleotides, CGG repeat binding molecules, histone acetyltransferase inhibitors, heat shock proteins and heat shock response inducers have therapeutic potential.
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CGG repeat expansion diseases might represent manifestations of an underlying non-coding CGG expansion neuromyodegenerative syndrome in which different organs are affected to varying degrees according to the gene location of the repeat expansion.
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References
Richard, G. F., Kerrest, A. & Dujon, B. Comparative genomics and molecular dynamics of DNA repeats in eukaryotes. Microbiol. Mol. Biol. Rev. 72, 686–727 (2008).
Richards, R. I. Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum. Mol. Genet. 10, 2187–2194 (2001).
Paulson, H. Repeat expansion diseases. Handb. Clin. Neurol. 147, 105–123 (2018).
Almeida, B., Fernandes, S., Abreu, I. A. & Macedo-Ribeiro, S. Trinucleotide repeats: a structural perspective. Front. Neurol. 4, 76 (2013).
Hagerman, R. J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127–130 (2001).
Murray, A., Webb, J., Grimley, S., Conway, G. & Jacobs, P. Studies of FRAXA and FRAXE in women with premature ovarian failure. J. Med. Genet. 35, 637–640 (1998).
Ishiura, H. et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlap** disease. Nat. Genet. 51, 1222–1232 (2019). This study was the first to demonstrate the association between CGG repeat expansions in genes and NIID, OPML and OPDM.
Sone, J. et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat. Genet. 51, 1215–1221 (2019).
Tian, Y. et al. Expansion of human-specific GGC repeat in neuronal intranuclear inclusion disease-related disorders. Am. J. Hum. Genet. 105, 166–176 (2019).
Deng, J. et al. Expansion of GGC repeat in GIPC1 is associated with oculopharyngodistal myopathy. Am. J. Hum. Genet. 106, 793–804 (2020). This study was the first to demonstrate the association between CGG expansions in the GIPC1 gene and OPDM.
Fu, Y. H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).
Darnell, J. C. & Klann, E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat. Neurosci. 16, 1530–1536 (2013).
Loesch, D. & Hagerman, R. Unstable mutations in the FMR1 gene and the phenotypes. Adv. Exp. Med. Biol. 769, 78–114 (2012).
Garcia-Arocena, D. & Hagerman, P. J. Advances in understanding the molecular basis of FXTAS. Hum. Mol. Genet. 19, R83–R89 (2010).
Jacquemont, S. et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291, 460–469 (2004).
Rodriguez-Revenga, L. et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur. J. Hum. Genet. 17, 1359–1362 (2009).
Cabal-Herrera, A. M., Tassanakijpanich, N., Salcedo-Arellano, M. J. & Hagerman, R. J. Fragile X-associated tremor/ataxia syndrome (FXTAS): pathophysiology and clinical implications. Int. J. Mol. Sci. 21, 4391 (2020).
Jacquemont, S. et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am. J. Hum. Genet. 72, 869–878 (2003).
Zafarullah, M. & Tassone, F. Fragile X-associated tremor/ataxia syndrome (FXTAS). Methods Mol. Biol. 1942, 173–189 (2019).
Gelpi, E. et al. Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. Brain 140, e51 (2017).
Lechpammer, M. et al. Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases. Croat. Med. J. 58, 310–315 (2017).
Godler, D. E. et al. Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. Hum. Mol. Genet. 19, 1618–1632 (2010).
Schneider, A. et al. Elevated FMR1-mRNA and lowered FMRP–a double-hit mechanism for psychiatric features in men with FMR1 premutations. Transl. Psychiatry 10, 205 (2020).
Sung, J. H., Ramirez-Lassepas, M., Mastri, A. R. & Larkin, S. M. An unusual degenerative disorder of neurons associated with a novel intranuclear hyaline inclusion (neuronal intranuclear hyaline inclusion disease). A clinicopathological study of a case. J. Neuropathol. Exp. Neurol. 39, 107–130 (1980).
Suzuki, I. K. et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Cell 173, 1370–1384.e16 (2018).
Fiddes, I. T. et al. Human-specific NOTCH2NL genes affect notch signaling and cortical neurogenesis. Cell 173, 1356–1369.e22 (2019).
Sone, J. et al. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain 139, 3170–3186 (2016).
Liang, H. et al. Clinical and pathological features in adult-onset NIID patients with cortical enhancement. J. Neurol. 267, 3187–3198 (2020).
Yau, W. Y. et al. Low prevalence of NOTCH2NLC GGC repeat expansion in white patients with movement disorders. Mov. Disord. 36, 251–255 (2021).
Chen, L. et al. A long time radiological follow-up of neuronal intranuclear inclusion disease: two case reports. Medicine 97, e13544 (2018).
Sone, J. et al. Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy. Neurology 65, 1538–1543 (2005).
Chintalaphani, S. R., Pineda, S. S., Deveson, I. W. & Kumar, K. R. An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics. Acta Neuropathol. Commun. 9, 98 (2021).
Ma, D. et al. Association of NOTCH2NLC repeat expansions with parkinson disease. JAMA Neurol. 77, 1559–1563 (2020). This was the first study to identify CGG expansions in NOTCH2NLC in patients with PD.
Greco, C. M. et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129, 243–255 (2006).
Woulfe, J. M. Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress. Neuropathol. Appl. Neurobiol. 33, 2–42 (2007).
Okamura, S. et al. A case of neuronal intranuclear inclusion disease with recurrent vomiting and without apparent DWI abnormality for the first seven years. Heliyon 6, e04675 (2020).
Wenzel, H. J., Hunsaker, M. R., Greco, C. M., Willemsen, R. & Berman, R. F. Ubiquitin-positive intranuclear inclusions in neuronal and glial cells in a mouse model of the fragile X premutation. Brain Res. 1318, 155–166 (2010).
Sun, Q. Y. et al. Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain 143, 222–233 (2020). This study was the first to demonstrate the association between CGG expansions in NOTCH2NLC and essential tremor.
Ng, A. S. L. et al. NOTCH2NLC GGC repeat expansions are associated with sporadic essential tremor: variable disease expressivity on long-term follow-up. Ann. Neurol. 88, 614–618 (2020).
Fang, P. et al. Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy. Ann. Clin. Transl. Neurol. 7, 517–526 (2020).
Hayashi, T. et al. Heterozygous GGC repeat expansion of NOTCH2NLC in a patient with neuronal intranuclear inclusion disease and progressive retinal dystrophy. Ophthalmic Genet. 41, 93–95 (2020).
Jiao, B. et al. Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias. Neurobiol. Aging 89, 142.e1–142.e7 (2020). The study was the first to demonstrate of the association between CGG expansions in NOTCH2NLC and dementia.
Okubo, M. et al. GGC repeat expansion of NOTCH2NLC in adult patients with leukoencephalopathy. Ann. Neurol. 86, 962–968 (2019).
Yuan, Y. et al. Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis. Neurology 95, e3394–e3405 (2020). This study was the first to demonstrate CGG expansions in NOTCH2NLC as the cause of amyotrophic lateral sclerosis.
Ogasawara, M. et al. CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations. Acta Neuropathol. Commun. 8, 204 (2020). This was the first study to link CGG expansions in NOTCH2NLC with OPDM.
Battle, M. A., Maher, V. M. & McCormick, J. J. ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways. Biochemistry 42, 7270–7282 (2003).
Lee, N. Y., Ray, B., How, T. & Blobe, G. C. Endoglin promotes transforming growth factor β-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J. Biol. Chem. 283, 32527–32533 (2008).
Von Kap-Herr, C. et al. Assignment of PDZ domain-containing protein GIPC gene (C19orf3) to human chromosome band 19p13.1 by in situ hybridization and radiation hybrid map**. Cytogenet. Cell Genet. 89, 234–235 (2000).
Durmus, H. et al. Oculopharyngodistal myopathy is a distinct entity: clinical and genetic features of 47 patients. Neurology 76, 227–235 (2011).
Saito, R. et al. Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP12. Acta Neuropathol. Commun. 8, 75 (2020).
Kong, H. E., Zhao, J., Xu, S., **, P. & **, Y. Fragile X-associated tremor/ataxia syndrome: from molecular pathogenesis to development of therapeutics. Front. Cell Neurosci. 11, 128 (2017).
Rodriguez, C. M. & Todd, P. K. New pathologic mechanisms in nucleotide repeat expansion disorders. Neurobiol. Dis. 130, 104515 (2019).
Hagerman, P. J. & Hagerman, R. J. The fragile-X premutation: a maturing perspective. Am. J. Hum. Genet. 74, 805–816 (2004).
Santa Maria, L. et al. FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile. Clin. Genet. 86, 378–382 (2014).
Brouwer, J. R. et al. Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated fragile X full mutation. Exp. Cell Res. 313, 244–253 (2007).
Liu, Y., Winarni, T. I., Zhang, L., Tassone, F. & Hagerman, R. J. Fragile X-associated tremor/ataxia syndrome (FXTAS) in grey zone carriers. Clin. Genet. 84, 74–77 (2012).
Galloway, J. N. & Nelson, D. L. Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome. Future Neurol. 4, 785 (2009).
Castro, H. et al. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of fragile X-associated tremor/ataxia syndrome. Hum. Mol. Genet. 26, 2133–2145 (2017).
Willemsen, R. et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum. Mol. Genet. 12, 949–959 (2003).
Drozd, M. et al. Reduction of Fmr1 mRNA levels rescues pathological features in cortical neurons in a model of FXTAS. Mol. Ther. Nucleic Acids 18, 546–553 (2019).
Burguete, A. S. et al. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4, e08881 (2015).
Nussbacher, J. K., Tabet, R., Yeo, G. W. & Lagier-Tourenne, C. Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron 102, 294–320 (2019).
Derbis, M. et al. Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats. Nat. Commun. 12, 1265 (2021).
Hoem, G. et al. CGG-repeat length threshold for FMR1 RNA pathogenesis in a cellular model for FXTAS. Hum. Mol. Genet. 20, 2161–2170 (2011).
Ajjugal, Y., Kolimi, N. & Rathinavelan, T. Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS. Sci. Rep. 11, 8163 (2021).
Pearson, C. E. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet. 7, e1002018 (2011).
Kearse, M. G. et al. CGG repeat-associated non-AUG translation utilizes a cap-dependent scanning mechanism of initiation to produce toxic proteins. Mol. Cell 62, 314–322 (2016).
Green, K. M., Linsalata, A. E. & Todd, P. K. RAN translation–what makes it run? Brain Res. 1647, 30–42 (2016).
Boivin, M. et al. Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: the polyG diseases. Neuron 109, 1825–1835.e5 (2021).
Kozak, M. Features in the 5′ non-coding sequences of rabbit α and β-globin mRNAs that affect translational efficiency. J. Mol. Biol. 235, 95–110 (1994).
Kozak, M. Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proc. Natl Acad. Sci. USA 87, 8301–8305 (1990).
Todd, P. K. et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78, 440–455 (2013).
Uversky, V. N. & Dunker, A. K. Understanding protein non-folding. Biochim. Biophys. Acta 1804, 1231–1264 (2010).
Darling, A. L. & Uversky, V. N. Intrinsic disorder in proteins with pathogenic repeat expansions. Molecules 22, 2027 (2017).
Dougan, L., Li, J., Badilla, C. L., Berne, B. J. & Fernandez, J. M. Single homopolypeptide chains collapse into mechanically rigid conformations. Proc. Natl Acad. Sci. USA 106, 12605–12610 (2009).
Gohel, D. et al. FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 1379–1388 (2017).
Krans, A., Kearse, M. G. & Todd, P. K. Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome. Ann. Neurol. 80, 871–881 (2016).
Oh, S. Y. et al. RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome. Hum. Mol. Genet. 24, 4317–4326 (2015).
Hukema, R. K. et al. Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Hum. Mol. Genet. 24, 4948–4957 (2015).
Cheng, W. et al. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat. Commun. 9, 51 (2018).
Green, K. M. et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat. Commun. 8, 2005 (2017).
Asamitsu, S. et al. CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. Sci. Adv. 7, eabd9440 (2021).
Ma, L. et al. Composition of the intranuclear inclusions of fragile X-associated/ataxia syndrome. Acta Neuropathol. Commun. 7, 143 (2019).
Nobile, V. et al. Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene. Hum. Genet. 139, 227–245 (2020).
Ross-Inta, C. et al. Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem. J. 429, 545–552 (2010).
Napoli, E. et al. Warburg effect linked to cognitive-executive deficits in FMR1 premutation. FASEB J. 30, 3334–3351 (2016).
Napoli, E. et al. Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. Hum. Mol. Genet. 20, 3079–3092 (2011).
Kaplan, E. S. et al. Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre-mutation mouse model. J. Neurochem. 123, 613–621 (2012).
Mouchiroud, L. et al. The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
Kozlov, A. V., Lancaster, J. R. Jr., Meszaros, A. T. & Weidinger, A. Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol. 13, 170–181 (2017).
Dolzhenko, E. et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 21, 102 (2020).
Giesselmann, P. et al. Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing. Nat. Biotechnol. 37, 1478–1481 (2019).
Doi, K. et al. Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing. Bioinformatics 30, 815–822 (2014).
Hafford-Tear, N. J. et al. CRISPR/Cas9-targeted enrichment and long-read sequencing of the Fuchs endothelial corneal dystrophy-associated TCF4 triplet repeat. Genet. Med. 21, 2092–2102 (2019).
Chiara, M., Zambelli, F., Picardi, E., Horner, D. S. & Pesole, G. Critical assessment of bioinformatics methods for the characterization of pathological repeat expansions with single-molecule sequencing data. Brief. Bioinform 21, 1971–1986 (2020).
Mitsuhashi, S. & Matsumoto, N. Long-read sequencing for rare human genetic diseases. J. Hum. Genet. 65, 11–19 (2020).
Juang, B. T. et al. Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans. Hum. Mol. Genet. 23, 4945–4959 (2014).
Ludwig, A. L. et al. CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size. Hum. Mol. Genet. 23, 3228–3238 (2014).
Diep, A. A. et al. Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task. Neurobiol. Learn Mem. 97, 229–234 (2012).
Foote, M. M., Careaga, M. & Berman, R. F. What has been learned from mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome? Clin. Neuropsychol. 30, 960–972 (2016).
Csobonyeiova, M., Polak, S. & Danisovic, L. Recent overview of the use of iPSCs Huntington’s disease modeling and therapy. Int. J. Mol. Sci. 21, 2239 (2020).
Conforti, P. et al. Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes. Proc. Natl Acad. Sci. USA 115, E762–E771 (2018).
Qian, X., Song, H. & Ming, G. L. Brain organoids: advances, applications and challenges. Development 146, dev166074 (2019).
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018).
Crespan, E., Hubscher, U. & Maga, G. Expansion of CAG triplet repeats by human DNA polymerases λ and β in vitro, is regulated by flap endonuclease 1 and DNA ligase 1. DNA Repair 29, 101–111 (2015).
Deshmukh, A. L. et al. FAN1, a DNA repair nuclease, as a modifier of repeat expansion disorders. J. Huntingt. Dis. 10, 95–122 (2021).
Flower, M. et al. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 142, 1876–1886 (2019).
Napierala, M., Michalowski, D., de Mezer, M. & Krzyzosiak, W. J. Facile FMR1 mRNA structure regulation by interruptions in CGG repeats. Nucleic Acids Res. 33, 451–463 (2005).
Chen, Z. et al. Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort. Clin. Genet. 98, 274–281 (2020).
Miller, C. M. & Harris, E. N. Antisense oligonucleotides: treatment strategies and cellular internalization. RNA Dis. 3, e1393 (2016).
Rodriguez, C. M. et al. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nat. Neurosci. 23, 386–397 (2020).
Tran, T. et al. Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides. ACS Chem. Biol. 9, 904–912 (2014).
Disney, M. D. et al. A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome. ACS Chem. Biol. 7, 1711–1718 (2012).
Yoshida, T. et al. Evaluation of off-target effects of gapmer antisense oligonucleotides using human cells. Genes Cell 24, 827–835 (2019).
Angelbello, A. J., DeFeo, M. E., Glinkerman, C. M., Boger, D. L. & Disney, M. D. Precise targeted cleavage of a r(CUG) repeat expansion in cells by using a small-molecule-deglycobleomycin conjugate. ACS Chem. Biol. 15, 849–855 (2020).
Siboni, R. B. et al. Actinomycin D specifically reduces expanded CUG repeat RNA in myotonic dystrophy models. Cell Rep. 13, 2386–2394 (2015).
Annear, D. J. et al. Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease. Sci. Rep. 11, 2515 (2021).
Hu, J. et al. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat. Biotechnol. 27, 478–484 (2009).
Sellier, C. et al. Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome. Cell Rep. 3, 869–880 (2013).
Sofola, O. A. et al. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55, 565–571 (2007).
**, P. et al. Pur α binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55, 556–564 (2007).
Todd, P. K. et al. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet. 6, e1001240 (2010).
Mosbach, V., Poggi, L. & Richard, G. F. Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy. Curr. Genet. 65, 17–28 (2019).
Cinesi, C., Aeschbach, L., Yang, B. & Dion, V. Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase. Nat. Commun. 7, 13272 (2016).
An, M. C. et al. Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11, 253–263 (2012).
Li, J. et al. Naphthyridine-benzoazaquinolone: evaluation of a tricyclic system for the binding to (CAG)n repeat DNA and RNA. Chem. Asian J. 11, 1971–1981 (2016).
Robin, G. et al. Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome. Hum. Mol. Genet. 26, 2649–2666 (2017).
Kumari, D. et al. The role of DNA damage response pathways in chromosome fragility in fragile X syndrome. Nucleic Acids Res. 37, 4385–4392 (2009).
Casper, A. M., Nghiem, P., Arlt, M. F. & Glover, T. W. ATR regulates fragile site stability. Cell 111, 779–789 (2002).
Ozeri-Galai, E., Schwartz, M., Rahat, A. & Kerem, B. Interplay between ATM and ATR in the regulation of common fragile site stability. Oncogene 27, 2109–2117 (2008).
Entezam, A. & Usdin, K. ATR protects the genome against CGG.CCG-repeat expansion in fragile X premutation mice. Nucleic Acids Res. 36, 1050–1056 (2008).
McKinnon, C. et al. Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system. Acta Neuropathol. 131, 411–425 (2015).
Ryno, L. M., Wiseman, R. L. & Kelly, J. W. Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. Curr. Opin. Chem. Biol. 17, 346–352 (2013).
Banerjee, A., Apponi, L. H., Pavlath, G. K. & Corbett, A. H. PABPN1: molecular function and muscle disease. Febs J. 280, 4230–4250 (2013).
Shi, C. et al. The inhibition of heat shock protein 90 facilitates the degradation of poly-alanine expanded poly (A) binding protein nuclear 1 via the carboxyl terminus of heat shock protein 70-interacting protein. PLoS ONE 10, e0138936 (2015).
Abu-Baker, A. et al. Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy. Hum. Mol. Genet. 12, 2609–2623 (2003).
Perie, S. et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol. Ther. 22, 219–225 (2014).
Cho, I. K., Hunter, C. E., Ye, S., Pongos, A. L. & Chan, A. W. S. Combination of stem cell and gene therapy ameliorates symptoms in Huntington’s disease mice. NPJ Regen. Med. 4, 7 (2019).
Danielyan, L. et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res. 14, 3–16 (2011).
Yu-Taeger, L. et al. Intranasal administration of mesenchymal stem cells ameliorates the abnormal dopamine transmission system and inflammatory reaction in the R6/2 mouse model of Huntington disease. Cells 8, 595 (2019).
Santamaria, G. et al. Intranasal delivery of mesenchymal stem cell secretome repairs the brain of Alzheimer’s mice. Cell Death Differ. 28, 203–218 (2020).
Olejniczak, M., Urbanek, M. O. & Krzyzosiak, W. J. The role of the immune system in triplet repeat expansion diseases. Med. Inflamm. 2015, 873860 (2015).
Switonski, P. M., Szlachcic, W. J., Gabka, A., Krzyzosiak, W. J. & Figiel, M. Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II. Mol. Neurobiol. 46, 430–466 (2012).
Bouchard, J. et al. Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. J. Neurosci. 32, 18259–18268 (2012).
Zwilling, D. et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145, 863–874 (2011).
Abu-Baker, A. & Rouleau, G. A. Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies. Biochim. Biophys. Acta 1772, 173–185 (2007).
Deng, J. et al. Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. J. Med. Genet. 56, 758–764 (2019).
van der Sluijs, B. M., ter Laak, H. J., Scheffer, H., van der Maarel, S. M. & van Engelen, B. G. Autosomal recessive oculopharyngodistal myopathy: a distinct phenotypical, histological, and genetic entity. J. Neurol. Neurosurg. Psychiatry 75, 1499–1501 (2004).
Acknowledgements
We thank the Singapore National Medical Research Council for providing funding support to E.-K.T. and Z.-D.Z. The authors are supported by Singapore National Medical Research Council (NMRC) (Clinical and Translational Research in Movement Disorders, NMRC/STaR/0030/2018 and Singapore Parkinson’s Disease Translational Clinical Program (SPARK II), MOH-OFLCG18May-0002).
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E.-K.T. researched data for the article. Z.-D.Z. and E.-K.T. wrote the manuscript. All authors made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.
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Zhou, ZD., Jankovic, J., Ashizawa, T. et al. Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions. Nat Rev Neurol 18, 145–157 (2022). https://doi.org/10.1038/s41582-021-00612-7
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DOI: https://doi.org/10.1038/s41582-021-00612-7
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