DNA damage and chromatin rearrangement in promoting neurodegeneration: role of hallmark proteins

Abstract

Numerous genetic and environmental factors contribute to neurodegenerative diseases characterized by damage to the DNA and changes in the chromatin structure. Many studies have shown that DNA damage and chromatin organization are closely linked, but more research is needed to fully understand this connection, especially in neurodegenerative diseases. Important proteins implicated in neurodegenerative disorders have been linked to chromatin reconfiguration and DNA damage, according to recent research. Epigenetic interventions such as HDAC inhibitors approved for cancer therapy, can be repurposed for neurodegenerative diseases. Furthermore, microRNAs, often dysregulated in neurodegenerative conditions, could be targeted to restore normal gene regulation. Exploring these strategies could lead to more effective treatments by addressing the fundamental epigenetic and chromatin-related mechanisms involved in neurodegeneration. This review discusses the relationship between the contributing proteins and various neurodegenerative diseases, with particular attention to key proteins like tau, which is associated with microtubules, superoxide dismutase 1, huntingtin, α-synuclein, β-amyloid precursor protein and TAR DNA/RNA binding protein 43 and their role in DNA protection and damage repair.

Keywords

Neurodegenerative diseases / DNA damage / Chromatin organization / Hallmark proteins / Neurological disorders

References

[1] Aricthota S, Rana PP, Haldar D. Histone acetylation dynamics in repair of DNA double-strand breaks. Frontiers in Genetics, 2022, 13

[2] Bampton A, Gittings LM, Fratta P, Lashley T, Gatt A. The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis. Acta Neuropathologica, 2020, 140(5): 599-623

[3] Benhelli-Mokrani H, Mansuroglu Z, Chauderlier A, Albaud B, Gentien D, Sommer S, Schirmer C, Laqueuvre L, Josse T, Buée L. Genome-wide identification of genic and intergenic neuronal DNA regions bound by Tau protein under physiological and stress conditions. Nucleic Acids Research, 2018, 46(21): 11405-11422

[4] Boutajangout A, Sigurdsson EM, Krishnamurthy K, P. . Tau as a therapeutic target for Alzheimer’s disease. Current Alzheimer Research, 2011, 8(6): 666-677

[5] Chantalat S, Depaux A, Héry P, Barral S, Thuret J-Y, Dimitrov S, Gérard M. Histone H3 trimethylation at lysine 36 is associated with constitutive and facultative heterochromatin. Genome Research, 2011, 21(9): 1426-1437

[6] Chen Y, Yu Y. Tau and neuroinflammation in Alzheimer’s disease: Interplay mechanisms and clinical translation. Journal of Neuroinflammation, 2023, 20(1): 165

[7] Costa RG, Conceição A, Matos CA, Nóbrega C. The polyglutamine protein ATXN2: From its molecular functions to its involvement in disease. Cell Death and Disease, 2024, 15(6): 415

[8] Fujii J, Homma T, Osaki T. Superoxide radicals in the execution of cell death. Antioxidants, 2022, 11(3): 501

[9] Gao R, Chakraborty A, Geater C, Pradhan S, Gordon KL, Snowden J, Yuan S, Dickey AS, Choudhary S, Ashizawa T. Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. eLife, 2019, 8

[10] Gimenez J, Spalloni A, Cappelli S, Ciaiola F, Orlando V, Buratti E, Longone P. TDP-43 epigenetic facets and their neurodegenerative implications. International Journal of Molecular Sciences, 2023, 24(18): 13807

[11] Gomes TM, Sousa P, Campos C, Perestrelo R, Câmara JS. Secondary bioactive metabolites from foods of plant origin as theravention agents against neurodegenerative disorders. Foods, 2024, 13(14): 2289

[12] Gong J, Huang M, Wang F, Ma X, Liu H, Tu Y, Xing L, Zhu X, Zheng H, Fang J. RBM45 competes with HDAC1 for binding to FUS in response to DNA damage. Nucleic Acids Research, 2017, 45(22): 12862-12876

[13] Goodnight AV, Kremsky I, Khampang S, Jung YH, Billingsley JM, Bosinger SE, Corces VG, Chan AWS. Chromatin accessibility and transcription dynamics during in vitro astrocyte differentiation of Huntington’s disease monkey pluripotent stem cells. Epigenetics and Chromatin, 2019, 12: 1-25

[14] Hitchler MJ, Domann FE. The epigenetic and morphogenetic effects of molecular oxygen and its derived reactive species in development. Free Radical Biology and Medicine, 2021, 170: 70-84

[15] Hwang YJ, Hyeon SJ, Kim Y, Lim S, Lee MY, Kim J, Londhe AM, Gotina L, Kim Y, Pae AN. Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington’s disease mouse model. Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(1): 856-868

[16] Jagaraj CJ, Shadfar S, Kashani SA, Saravanabavan S, Farzana F, Atkin JD. Molecular hallmarks of ageing in amyotrophic lateral sclerosis. Cellular and Molecular Life Sciences, 2024, 81(1): 111

[17] Jo M, Lee S, Jeon Y-M, Kim S, Kwon Y, Kim H-J. The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies. Experimental and Molecular Medicine, 2020, 52(10): 1652-1662

[18] Klaric JA, Wüst S, Panier S. New faces of old friends: Emerging new roles of RNA-binding proteins in the DNA double-strand break response. Frontiers in Molecular Biosciences, 2021, 8

[19] Konopka A, Atkin JD. The role of DNA damage in neural plasticity in physiology and neurodegeneration. Frontiers in Cellular Neuroscience, 2022, 16

[20] Li JY, Popovic N, Brundin P. The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx, 2005, 2(3): 447-464

[21] Liu L, Tong H, Sun Y, Chen X, Yang T, Zhou G, Li X-J, Li S. Huntingtin interacting proteins and pathological implications. International Journal of Molecular Sciences, 2023, 24(17): 13060

[22] Liu R, Wu J, Guo H, Yao W, Li S, Lu Y, Jia Y, Liang X, Tang J, Zhang H. Post-translational modifications of histones: Mechanisms, biological functions, and therapeutic targets. MedComm, 2023, 4(3):

[23] Mariño-Ramírez L, Kann MG, Shoemaker BA, Landsman D. Histone structure and nucleosome stability. Expert Review of Proteomics, 2005, 2(5): 719-729

[24] Mateos-Aparicio P, Rodríguez-Moreno A. The impact of studying brain plasticity. Frontiers in Cellular Neuroscience, 2019, 13: 66

[25] McCarthy RL, Kaeding KE, Keller SH, Zhong Y, Xu L, Hsieh A, Hou Y, Donahue G, Becker JS, Alberto O. Diverse heterochromatin-associated proteins repress distinct classes of genes and repetitive elements. Nature Cell Biology, 2021, 23(8): 905-914

[26] Nacev BA, Dabas Y, Paul MR, Pacheco C, Mitchener M, Perez Y, Fang Y, Soshnev AA, Barrows D, Carroll T. Cancer-associated histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation. Nature Communications, 2024, 15(1): 5155

[27] Niu Y, Pal A, Szewczyk B, Japtok J, Naumann M, Glaß H, Hermann A. Cell-type-dependent recruitment dynamics of FUS protein at laser-induced DNA damage sites. International Journal of Molecular Sciences, 2024, 25(6): 3526

[28] Orobets KS, Karamyshev AL. Amyloid precursor protein and Alzheimer’s disease. International Journal of Molecular Sciences, 2023, 24(19): 14794

[29] Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue Y-Q, Morabito S, Pan J, Oberhauser J, Madira AE, Shakouri T. Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron, 2022, 110(18): 2929-2948

[30] Provasek VE, Bacolla A, Rangaswamy S, Mitra J, Kodavati M, Yusuf IO, Malojirao VH, Vasquez V, Britz GW, Li G-M (2024) RNA/DNA binding protein TDP43 regulates DNA mismatch repair genes with implications for genome stability. BioRxiv

[31] Rane JS, Kumari A, Panda D. The acetyl mimicking mutation, K274Q in tau, enhances the metal binding affinity of tau and reduces the ability of tau to protect DNA. ACS Chemical Neuroscience, 2019, 11(3): 291-303

[32] Roberts A, Swerdlow RH, Wang N. Adaptive and maladaptive DNA breaks in neuronal physiology and Alzheimer’s disease. International Journal of Molecular Sciences, 2024, 25(14): 7774

[33] Sharma H. DNA damage and chromatin rearrangement work together to promote neurodegeneration.. Molecular Neurobiology, 2024, 2024: 1-19

[34] Shishido R, Kunii Y, Hino M, Izumi R, Nagaoka A, Hayashi H, Kakita A, Tomita H, Yabe H. Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia. Frontiers in Psychiatry, 2023, 14: 1183696

[35] Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Research, 2008, 18(1): 134-147

[36] Shukla S, Tekwani BL. Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation. Frontiers in Pharmacology, 2020, 11: 537

[37] Shum C, Hedges EC, Allison J, Lee Y, Arias N, Cocks G, Chandran S, Ruepp M-D, Shaw CE, Nishimura AL. Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons. Stem Cell Reports, 2024, 19(2): 187-195

[38] Song H, Shen R, Liu X, Yang X, Xie K, Guo Z, Wang D. Histone post-translational modification and the DNA damage response. Genes and Diseases, 2023, 10(4): 1429-1444

[39] Sugeno N, Hasegawa T. Unraveling the complex interplay between alpha-synuclein and epigenetic modification. International Journal of Molecular Sciences, 2023, 24(7): 6645

[40] Sun X, Gao C, Xu X, Li M, Zhao X, Wang Y, Wang Y, Zhang S, Yan Z, Liu X. FBL promotes cancer cell resistance to DNA damage and BRCA1 transcription via YBX1. EMBO Reports, 2023, 24(9):

[41] Surguchov A. α-Synuclein and mechanisms of epigenetic regulation. Brain Sciences, 2023, 13(1): 150

[42] Suzuki N, Nishiyama A, Warita H, Aoki M. Genetics of amyotrophic lateral sclerosis: Seeking therapeutic targets in the era of gene therapy. Journal of Human Genetics, 2023, 68(3): 131-152

[43] Tiwari V, Wilson DM. DNA damage and associated DNA repair defects in disease and premature aging. The American Journal of Human Genetics, 2019, 105(2): 237-257

[44] Welch G, Tsai L. Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease. EMBO Reports, 2022, 23(6):

[45] Wiench M, Miranda TB, Hager GL. Control of nuclear receptor function by local chromatin structure. The FEBS Journal, 2011, 278(13): 2211-2230

[46] Xiao W, Zhou Q, Wen X, Wang R, Liu R, Wang T, Shi J, Hu Y, Hou J. Small-molecule inhibitors overcome epigenetic reprogramming for cancer therapy. Frontiers in Pharmacology, 2021, 12

[47] Yabata H, Riku Y, Miyahara H, Akagi A, Sone J, Urushitani M, Yoshida M, Iwasaki Y. Nuclear expression of TDP-43 is linked with morphology and ubiquitylation of cytoplasmic aggregates in amyotrophic lateral sclerosis. International Journal of Molecular Sciences, 2023, 24(15): 12176

[48] Yazar V, Kühlwein JK, Knehr A, Grozdanov V, Ekici AB, Ludolph AC, Danzer KM. Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients. Scientific Reports, 2023, 13(1): 12019