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Molecular Neurodegeneration
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Open Access 01-12-2024 | Parkinson Disease | Research article

NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson’s disease-like phenotypes in mice

Authors: Haitao Tu, Xin Yi Yeo, Zhi-Wei Zhang, Wei Zhou, Jayne Yi Tan, Li Chi, Sook-Yoong Chia, Zhihong Li, Aik Yong Sim, Brijesh Kumar Singh, Dongrui Ma, Zhidong Zhou, Isabelle Bonne, Shuo-Chien Ling, Adeline S.L. Ng, Sangyong Jung, Eng-King Tan, Li Zeng

Published in: Molecular Neurodegeneration | Issue 1/2024

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Abstract

Background

The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored.

Methods

Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs.

Results

Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex.

Conclusions

Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.
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Literature
1.
Okubo M, Doi H, Fukai R, Fujita A, Mitsuhashi S, Hashiguchi S, Kishida H, Ueda N, Morihara K, Ogasawara A, et al. GGC repeat expansion of NOTCH2NLC in adult patients with Leukoencephalopathy. Ann Neurol. 2019;86:962–8.PubMedCrossRef
2.
Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, Koike H, Hashiguchi A, Takashima H, Sugiyama H, et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet. 2019;51:1215–21.PubMedCrossRef
3.
Tian Y, Wang JL, Huang W, Zeng S, Jiao B, Liu Z, Chen Z, Li Y, Wang Y, Min HX, et al. Expansion of human-specific GGC repeat in neuronal intranuclear inclusion Disease-Related disorders. Am J Hum Genet. 2019;105:166–76.PubMedPubMedCentralCrossRef
4.
Jiao B, Zhou L, Zhou Y, Weng L, Liao X, Tian Y, Guo L, Liu X, Yuan Z, Xiao X, et al. Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias. Neurobiol Aging. 2020;89:142. e141-142 e147.CrossRef
5.
Ma D, Tan YJ, Ng ASL, Ong HL, Sim W, Lim WK, Teo JX, Ng EYL, Lim EC, Lim EW, et al. Association of NOTCH2NLC repeat expansions with Parkinson Disease. JAMA Neurol. 2020;77:1559–63.PubMedCrossRef
6.
Liu Q, Chen J, Xue J, Zhou X, Tian Y, Xiao Q, Huang W, Pan Y, Zhou X, Li J, et al. GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration. Eur J Neurol. 2024;31:e16145.PubMedCrossRef
7.
Ng ASL, Lim WK, Xu Z, Ong HL, Tan YJ, Sim WY, Ng EYL, Teo JX, Foo JN, Lim TCC, et al. NOTCH2NLC GGC repeat expansions are Associated with sporadic essential tremor: Variable Disease Expressivity on Long-Term follow-up. Ann Neurol. 2020;88:614–8.PubMedCrossRef
8.
Sun QY, Xu Q, Tian Y, Hu ZM, Qin LX, Yang JX, Huang W, Xue J, Li JC, Zeng S, et al. Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain. 2020;143:222–33.PubMedCrossRef
9.
Nakamura N, Tsunoda K, Mitsutake A, Shibata S, Mano T, Nagashima Y, Ishiura H, Iwata A, Toda T, Tsuji S, Sawamura H. Clinical characteristics of neuronal intranuclear inclusion disease-related retinopathy with CGG repeat expansions in the NOTCH2NLC Gene. Invest Ophthalmol Vis Sci. 2020;61:27.PubMedPubMedCentralCrossRef
10.
11.
Zhou ZD, Jankovic J, Ashizawa T, Tan EK. Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions. Nat Rev Neurol. 2022;18:145–57.PubMedCrossRef
12.
Huang XR, Tang BS, Jin P, Guo JF. The phenotypes and mechanisms of NOTCH2NLC-Related GGC repeat expansion disorders: a Comprehensive Review. Mol Neurobiol. 2022;59:523–34.PubMedCrossRef
13.
Boivin M, Deng J, Pfister V, Grandgirard E, Oulad-Abdelghani M, Morlet B, Ruffenach F, Negroni L, Koebel P, Jacob H, 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. 2021;109:1825–e18351825.PubMedPubMedCentralCrossRef
14.
15.
Zhong S, Lian Y, Luo W, Luo R, Wu X, Ji J, Ji Y, Ding J, Wang X. Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases. Acta Neuropathol. 2021;142:1003–23.PubMedCrossRef
16.
Suzuki IK, Gacquer D, Van Heurck R, Kumar D, Wojno M, Bilheu A, Herpoel A, Lambert N, Cheron J, Polleux F, et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch Regulation. Cell. 2018;173:1370–e13841316.PubMedPubMedCentralCrossRef
17.
Pang J, Yang J, Yuan Y, Gao Y, Shi C, Fan S, Xu Y. The value of NOTCH2NLC Gene detection and skin biopsy in the diagnosis of neuronal intranuclear inclusion disease. Front Neurol. 2021;12:624321.PubMedPubMedCentralCrossRef
18.
Wang H, Zheng Y, Yu J, Meng L, Zhang W, Hong D, Wang Z, Yuan Y, Deng J. Pathologic changes in neuronal intranuclear inclusion disease are linked to aberrant FUS interaction under hyperosmotic stress. Neurobiol Dis. 2024;190:106391.PubMedCrossRef
19.
Yu J, Liufu T, Zheng Y, Xu J, Meng L, Zhang W, Yuan Y, Hong D, Charlet-Berguerand N, Wang Z, Deng J. CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model. Proc Natl Acad Sci U S A. 2022;119:e2208649119.PubMedPubMedCentralCrossRef
20.
Liu Q, Zhang K, Kang Y, Li Y, Deng P, Li Y, Tian Y, Sun Q, Tang Y, Xu K, et al. Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease. Sci Adv. 2022;8:eadd6391.PubMedPubMedCentralCrossRef
21.
Zhong S, Lian Y, Zhou B, Ren R, Duan L, Pan Y, Gong Y, Wu X, Cheng D, Zhang P, et al. Microglia contribute to polyg-dependent neurodegeneration in neuronal intranuclear inclusion disease. Acta Neuropathol. 2024;148:21.PubMedCrossRef
22.
Pan Y, Jiang Y, Wan J, Hu Z, Jiang H, Shen L, Tang B, Tian Y, Liu Q. Expression of expanded GGC repeats within NOTCH2NLC causes cardiac dysfunction in mouse models. Cell Biosci. 2023;13:157.PubMedPubMedCentralCrossRef
23.
Fan Y, Li MJ, Yang J, Li SJ, Hao XY, Li JD, Wang YC, Tang MB, Zhang C, Shi JJ, et al. GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation. Brain. 2023;146:3373–91.PubMedCrossRef
24.
Lothian C, Lendahl U. An evolutionarily conserved region in the second intron of the human nestin gene directs gene expression to CNS progenitor cells and to early neural crest cells. Eur J Neurosci. 1997;9:452–62.PubMedCrossRef
25.
Roy NS, Benraiss A, Wang S, Fraser RA, Goodman R, Couldwell WT, Nedergaard M, Kawaguchi A, Okano H, Goldman SA. Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res. 2000;59:321–31.PubMedCrossRef
26.
Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, Wu S, Wang Y. SRplot: a free online platform for data visualization and graphing. PLoS ONE. 2023;18:e0294236.PubMedPubMedCentralCrossRef
27.
Jelisejevs I, Upite J, Kalnins S, Jansone B. An Improved Surgical Approach for Complete Interhemispheric Corpus Callosotomy Combined with extended Frontoparietal Craniotomy in mice. Biomedicines. 2023;11:1782.PubMedPubMedCentralCrossRef
28.
Schröder H, Moser N, Huggenberger S. Macroscopic anatomy of the mouse brain. Neuroanatomy of the mouse. Cham: Springer International Publishing; 2020. pp. 45–57.CrossRef
29.
Chaudhry A, Shi R, Luciani DS. A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2020;318:E87–101.PubMedCrossRef
30.
Klickstein JA, Mukkavalli S, Raman M. AggreCount: an unbiased image analysis tool for identifying and quantifying cellular aggregates in a spatially defined manner. J Biol Chem. 2020;295:17672–83.PubMedPubMedCentralCrossRef
31.
Chen ZC, Zhang W, Chua LL, Chai C, Li R, Lin L, Cao Z, Angeles DC, Stanton LW, Peng JH, et al. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci Signal. 2017;10:eaam6790.PubMedCrossRef
32.
Zhang ZW, Tu H, Jiang M, Vanan S, Chia SY, Jang SE, Saw WT, Ong ZW, Ma DR, Zhou ZD, et al. The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson’s disease. Sci Signal. 2022;15:eabk3411.PubMedCrossRef
33.
Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-Associated Tremor/Ataxia syndrome (FXTAS): pathophysiology and clinical implications. Int J Mol Sci 2020, 21.
34.
Hagerman RJ, Hagerman P. Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management. Nat Rev Neurol. 2016;12:403–12.PubMedCrossRef
35.
Asamitsu S, Yabuki Y, Ikenoshita S, Kawakubo K, Kawasaki M, Usuki S, Nakayama Y, Adachi K, Kugoh H, Ishii K, et al. CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. Sci Adv. 2021;7:eabd9440.PubMedPubMedCentralCrossRef
36.
Divakaruni AS, Jastroch M. A practical guide for the analysis, standardization and interpretation of oxygen consumption measurements. Nat Metab. 2022;4:978–94.PubMedPubMedCentralCrossRef
37.
Tu H, Zhang ZW, Qiu L, Lin Y, Jiang M, Chia SY, Wei Y, Ng ASL, Reynolds R, Tan EK, Zeng L. Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies. BMC Neurosci. 2022;23:3.PubMedPubMedCentralCrossRef
38.
Bueno-Carrasco MT, Cuellar J, Flydal MI, Santiago C, Krakenes TA, Kleppe R, Lopez-Blanco JR, Marcilla M, Teigen K, Alvira S, et al. Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Nat Commun. 2022;13:74.PubMedPubMedCentralCrossRef
39.
Grosch J, Winkler J, Kohl Z. Early Degeneration of both dopaminergic and serotonergic axons - a common mechanism in Parkinson’s Disease. Front Cell Neurosci. 2016;10:293.PubMedPubMedCentralCrossRef
40.
Zhang Q, Weber MA, Narayanan NS. Medial prefrontal cortex and the temporal control of action. Int Rev Neurobiol. 2021;158:421–41.PubMedCrossRef
41.
Jereissati LO, Silva LAd, Antoniol T, Coimbra VO, Silva AAd M, ARBd, Gomes GF, Galvão SL et al. Oliveira RWGd, Santos NLd, : The role of medial prefrontal cortex in cognition, aging and Parkinson disease. Brazilian Journal of Clinical Medicine and Review 2023;1:28–40.
42.
Narayanan NS, Rodnitzky RL, Uc EY. Prefrontal dopamine signaling and cognitive symptoms of Parkinson’s disease. Rev Neurosci. 2013;24:267–78.PubMedCrossRef
43.
Marquez JS, Hasan SS, Siddiquee MR, Luca CC, Mishra VR, Mari Z, Bai O. Neural correlates of freezing of gait in Parkinson’s disease: an electrophysiology mini-review. Front Neurol. 2020;11:571086.PubMedPubMedCentralCrossRef
44.
Jahanshahi M, Obeso I, Rothwell JC, Obeso JA. A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition. Nat Rev Neurosci. 2015;16:719–32.PubMedCrossRef
45.
Kamasawa N, Sik A, Morita M, Yasumura T, Davidson KG, Nagy JI, Rash JE. Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning. Neuroscience. 2005;136:65–86.PubMedCrossRef
46.
47.
48.
Calvo-Rodriguez M, Bacskai BJ. Mitochondria and Calcium in Alzheimer’s Disease: from cell signaling to neuronal cell death. Trends Neurosci. 2021;44:136–51.PubMedCrossRef
49.
50.
Zirngibl M, Assinck P, Sizov A, Caprariello AV, Plemel JR. Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination. Mol Neurodegener. 2022;17:34.PubMedPubMedCentralCrossRef
51.
Traka M, Arasi K, Avila RL, Podojil JR, Christakos A, Miller SD, Soliven B, Popko B. A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain. 2010;133:3017–29.PubMedPubMedCentralCrossRef
52.
Leicaj ML, Pasquini LA, Lima A, Gonzalez Deniselle MC, Pasquini JM, De Nicola AF, Garay LI. Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone-treated mice. J Neuroendocrinol. 2018;30:e12649.PubMedCrossRef
53.
Han X, Han M, Liu N, Xu J, Zhang Y, Zhang Y, Hong D, Zhang W. Adult-onset neuronal intranuclear inclusion disease presenting with typical MRI changes. Brain Behav. 2019;9:e01477.PubMedPubMedCentralCrossRef
54.
Huang Y, Jin G, Zhan QL, Tian Y, Shen L. Adult-onset neuronal intranuclear inclusion disease, with both stroke-like onset and encephalitic attacks: a case report. BMC Neurol. 2021;21:142.PubMedPubMedCentralCrossRef
55.
Xie S, Yang J, Huang S, Fan Y, Xu T, He J, Guo J, Ji X, Wang Z, Li P, et al. Disrupted myelination network in the cingulate cortex of Parkinson’s disease. IET Syst Biol. 2022;16:98–119.PubMedPubMedCentralCrossRef
56.
Romanelli E, Merkler D, Mezydlo A, Weil MT, Weber MS, Nikic I, Potz S, Meinl E, Matznick FE, Kreutzfeldt M, et al. Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model. Nat Commun. 2016;7:13275.PubMedPubMedCentralCrossRef
57.
Meyer N, Rinholm JE. Mitochondria in Myelinating Oligodendrocytes: Slow and Out of Breath? Metabolites 2021, 11.
58.
Gottle P, Groh J, Reiche L, Gruchot J, Rychlik N, Werner L, Samper Agrelo I, Akkermann R, Zink A, Prigione A, et al. Teriflunomide as a therapeutic means for myelin repair. J Neuroinflammation. 2023;20:7.PubMedPubMedCentralCrossRef
59.
McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, et al. Microglia regulate central nervous system myelin growth and integrity. Nature. 2023;613:120–9.PubMedCrossRef
60.
Adlkofer K, Martini R, Aguzzi A, Zielasek J, Toyka KV, Suter U. Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice. Nat Genet. 1995;11:274–80.PubMedCrossRef
61.
Deng J, Gu M, Miao Y, Yao S, Zhu M, Fang P, Yu X, Li P, Su Y, Huang 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. 2019;56:758–64.PubMedCrossRef
62.
Chen Z, Xu Z, Cheng Q, Tan YJ, Ong HL, Zhao Y, Lim WK, Teo JX, Foo JN, Lee HY, et al. Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a southeast Asian cohort. Clin Genet. 2020;98:274–81.PubMedCrossRef
63.
Fang P, Yu Y, Yao S, Chen S, Zhu M, Chen Y, Zou K, Wang L, Wang H, Xin L, et al. Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy. Ann Clin Transl Neurol. 2020;7:517–26.PubMedPubMedCentralCrossRef
64.
Tian Y, Zhou L, Gao J, Jiao B, Zhang S, Xiao Q, Xue J, Wang Y, Liang H, Liu Y, et al. Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease. J Neurol Neurosurg Psychiatry. 2022;93:1289–98.PubMedCrossRef
65.
Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994;8:88–94.PubMedCrossRef
66.
Wright GEB, Collins JA, Kay C, McDonald C, Dolzhenko E, Xia Q, Becanovic K, Drogemoller BI, Semaka A, Nguyen CM, et al. Length of uninterrupted CAG, Independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington Disease. Am J Hum Genet. 2019;104:1116–26.PubMedPubMedCentralCrossRef
67.
Menon RP, Nethisinghe S, Faggiano S, Vannocci T, Rezaei H, Pemble S, Sweeney MG, Wood NW, Davis MB, Pastore A, Giunti P. The role of interruptions in polyQ in the pathology of SCA1. PLoS Genet. 2013;9:e1003648.PubMedPubMedCentralCrossRef
68.
Choudhry S, Mukerji M, Srivastava AK, Jain S, Brahmachari SK. CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet. 2001;10:2437–46.PubMedCrossRef
69.
Tan EK. Autosomal dominant spinocerebellar ataxias: an Asian perspective. Can J Neurol Sci. 2003;30:361–7.PubMedCrossRef
70.
Perez BA, Shorrock HK, Banez-Coronel M, Zu T, Romano LE, Laboissonniere LA, Reid T, Ikeda Y, Reddy K, Gomez CM, et al. CCG*CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO Mol Med. 2021;13:e14095.PubMedPubMedCentralCrossRef
71.
72.
Genetic Modifiers of Huntington’s Disease C. Identification of genetic factors that modify clinical onset of Huntington’s Disease. Cell. 2015;162:516–26.CrossRef
73.
Jones L, Houlden H, Tabrizi SJ. DNA repair in the trinucleotide repeat disorders. Lancet Neurol. 2017;16:88–96.PubMedCrossRef
74.
Mason AG, Tome S, Simard JP, Libby RT, Bammler TK, Beyer RP, Morton AJ, Pearson CE, La Spada AR. Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum Mol Genet. 2014;23:1606–18.PubMedCrossRef
75.
Schmidt MHM, Pearson CE. Disease-associated repeat instability and mismatch repair. DNA Repair (Amst). 2016;38:117–26.PubMedCrossRef
76.
Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of Models of Parkinson’s Disease. Front NeuroSci 2016, 9.
77.
Zhang TD, Kolbe SC, Beauchamp LC, Woodbridge EK, Finkelstein DI, Burrows EL. How well do Rodent models of Parkinson’s Disease recapitulate early non-motor phenotypes? A systematic review. Biomedicines. 2022;10:3026.PubMedPubMedCentralCrossRef
78.
Reeve AK, Grady JP, Cosgrave EM, Bennison E, Chen C, Hepplewhite PD, Morris CM. Mitochondrial dysfunction within the synapses of substantia nigra neurons in Parkinson’s disease. Npj Parkinson’s Disease. 2018;4:9.PubMedPubMedCentralCrossRef
79.
Li M, Xu H, Chen G, Sun S, Wang Q, Liu B, Wu X, Zhou L, Chai Z, Sun X, et al. Impaired D2 receptor-dependent dopaminergic transmission in prefrontal cortex of awake mouse model of Parkinson’s disease. Brain. 2019;142:3099–115.PubMedCrossRef
80.
Stadelmann C, Timmler S, Barrantes-Freer A, Simons M. Myelin in the Central Nervous System: structure, function, and Pathology. Physiol Rev. 2019;99:1381–431.PubMedCrossRef
81.
Giger RJ, Venkatesh K, Chivatakarn O, Raiker SJ, Robak L, Hofer T, Lee H, Rader C. Mechanisms of CNS myelin inhibition: evidence for distinct and neuronal cell type specific receptor systems. Restor Neurol Neurosci. 2008;26:97–115.PubMedPubMedCentral
82.
Tu HY, Yuan BS, Hou XO, Zhang XJ, Pei CS, Ma YT, Yang YP, Fan Y, Qin ZH, Liu CF, Hu LF. Alpha-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease. Aging Cell. 2021;20:e13522.PubMedPubMedCentralCrossRef
83.
Emery B. Transcriptional and post-transcriptional control of CNS myelination. Curr Opin Neurobiol. 2010;20:601–7.PubMedCrossRef
84.
Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E. The role of Mitochondria in neurodegenerative diseases: the lesson from Alzheimer’s Disease and Parkinson’s Disease. Mol Neurobiol. 2020;57:2959–80.PubMedCrossRef
85.
Lacombe A, Scorrano L. The interplay between mitochondrial dynamics and autophagy: from a key homeostatic mechanism to a driver of pathology. Semin Cell Dev Biol. 2024;161–162:1–19.PubMedCrossRef
86.
Nicholls DG. Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr Mol Med. 2004;4:149–77.PubMedCrossRef
87.
López-Muguruza E, Matute C. Alterations of Oligodendrocyte and Myelin Energy Metabolism in multiple sclerosis. Int J Mol Sci 2023, 24.
88.
Nishida I, Yamada K, Sakamoto A, Wakabayashi T, Iwatsubo T. Chronic neuronal hyperexcitation exacerbates tau propagation in a mouse model of Tauopathy. Int J Mol Sci. 2024;25:9004.PubMedPubMedCentralCrossRef
89.
Deodato F, Sabatelli M, Ricci E, Mercuri E, Muntoni F, Sewry C, Naom I, Tonali P, Guzzetta F. Hypermyelinating neuropathy, mental retardation and epilepsy in a case of merosin deficiency. Neuromuscul Disord. 2002;12:392–8.PubMedCrossRef
90.
Almeida RG. The rules of attraction in Central Nervous System Myelination. Front Cell Neurosci 2018, 12.
Metadata
Title
NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson’s disease-like phenotypes in mice
Authors
Haitao Tu
Xin Yi Yeo
Zhi-Wei Zhang
Wei Zhou
Jayne Yi Tan
Li Chi
Sook-Yoong Chia
Zhihong Li
Aik Yong Sim
Brijesh Kumar Singh
Dongrui Ma
Zhidong Zhou
Isabelle Bonne
Shuo-Chien Ling
Adeline S.L. Ng
Sangyong Jung
Eng-King Tan
Li Zeng
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-024-00780-2

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