Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model
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Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). α-synuclein transgenic mice with short telomeres (αSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of α-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in αSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates α-synuclein pathology that is linked to limited microglia function in the brainstem.
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Mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and premature development of age-related pathologies from the second or third generation.
“In particular, mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and a premature development of age-related pathologies from the second or third generation [8, 18–20, 51, 70, 72, 101, 103]”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [103]
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- [15]Tremblay ME Lowery RL Majewska AK Microglial interactions with synapses are modulated by visual experience PLoS Biol 2011 8 e1000527 10.1371/journal.pbio.1000527 21072242 PMC2970556 · DOI · Paper page
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Parkinson’s Disease: From Pathogenesis to Pharmacogenomics
Cacabelos, R. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030551 · Cited by 559 · see citing works
Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases
Spittau, B. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00194 · Cited by 258 · see citing works
Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?
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Microglia Response During Parkinson’s Disease: Alpha-Synuclein Intervention
Ferreira, S. A., & Romero‐Ramos, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00247 · Cited by 220 · see citing works
Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson’s Disease
Jin, W. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9010257 · Cited by 196 · see citing works
Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein
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Post-translational modifications: Regulators of neurodegenerative proteinopathies
Gupta, R. V., Sahu, M., Srivastava, D., Tiwari, S., Ambasta, R. K., & Kumar, P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101336 · Cited by 124 · see citing works
Microglia in neurodegenerative diseases
Xu, Y., Jin, M.-Z., Yang, Z., & Jin, M.-Z. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.290881 · Cited by 118 · see citing works
Microglia: Brain cells on the move
Smolders, S., Kessels, S., Vangansewinkel, T., Rigo, J., Legendre, P., & Brône, B. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.04.001 · Cited by 114 · see citing works
Ageing in the brain: mechanisms and rejuvenating strategies
Gaspar-Silva, F., Trigo, D., & Magalhães, J. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04832-6 · Cited by 64 · see citing works
Madetko, N., Migda, B., Alster, P., Turski, P., Koziorowski, D., & Friedman, A. (2022) · Neurologia i Neurochirurgia Polska · doi:10.5603/pjnns.a2022.0014 · Cited by 51 · see citing works
Telomere Attrition in Neurodegenerative Disorders
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Neurons and Glia Interplay in α-Synucleinopathies
Mavroeidi, P., & Xilouri, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094994 · Cited by 52 · see citing works
Muddapu, V. R., & Chakravarthy, V. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-81185-9 · Cited by 47 · see citing works
Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases
Wells, C., Brennan, S. E., Keon, M., & Saksena, N. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00271 · Cited by 45 · see citing works
Suelves, N., Saleki, S., Ibrahim, T., Palomares, D., Moonen, S., Koper, M. J., Vrancx, C., Vadukul, D. M., Papadopoulos, N., Viceconte, N., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01578-x · Cited by 43 · see citing works
Neuroinflammaging: A Tight Line Between Normal Aging and Age-Related Neurodegenerative Disorders
Soraci, L., Corsonello, A., Paparazzo, E., Montesanto, A., Piacenza, F., Olivieri, F., Gambuzza, M. E., Savedra, E. V., Marino, S., Lattanzio, F., et al. (2024) · Aging and Disease · doi:10.14336/ad.2023.1001 · Cited by 46 · see citing works
Aged-Related Changes in Microglia and Neurodegenerative Diseases: Exploring the Connection
Borrajo, A. (2024) · Biomedicines · doi:10.3390/biomedicines12081737 · Cited by 36 · see citing works
Dorostgou, Z., Yadegar, N., Dorostgou, Z., Khorvash, F., & Vakili, O. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25094 · Cited by 35 · see citing works
The Hallmarks of Ageing in Microglia
Carr, L. M., Mustafa, S., & Collins‐Praino, L. E. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01564-y · Cited by 37 · see citing works
Gillispie, G. J., Sah, E., Krishnamurthy, S., Ahmidouch, M. Y., Zhang, B., & Orr, M. E. (2021) · Life · doi:10.3390/life11020153 · Cited by 32 · see citing works
CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation
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The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy
Caobi, A., Dutta, R. K., Garbinski, L. D., Esteban-López, M., Ceyhan, Y., Andre, M., Manevski, M., Ojha, C. R., Lapierre, J., Tiwari, S., et al. (2020) · Aging and Disease · doi:10.14336/ad.2019.0927 · Cited by 24 · see citing works
What telomeres teach us about MS
Miner, A. E., & Graves, J. (2021) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2021.103084 · Cited by 23 · see citing works
Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities
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Evans, J. R., Torres-Pérez, J. V., Petrazzini, M. E. M., Riley, R. J., & Brennan, C. H. (2021) · Scientific Reports · doi:10.1038/s41598-020-79615-1 · Cited by 20 · see citing works
Enhanced motivation to alcohol in transgenic mice expressing human α‐synuclein
Rotermund, C., Reolon, G. K., Leixner, S., Boden, C., Bilbao, A., & Kahle, P. J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14151 · Cited by 16 · see citing works
Self-citationAging: Epigenetic modifications
Mishra, S., Raval, M., Kachhawaha, A. S., Tiwari, B. S., & Tiwari, A. K. (2023) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2023.02.002 · Cited by 14 · see citing works
Role of Telomeres and Telomerase in Parkinson's Disease—A New Theranostics?
Vellingiri, B., Balasubramani, K., Iyer, M., Raj, N., Elangovan, A., Song, K., Yeo, H. C., Jayakumar, N., Kinoshita, M., Ravimanickam, T., et al. (2023) · Advanced Biology · doi:10.1002/adbi.202300097 · Cited by 14 · see citing works
Wu, Y., Pei, Y., Yang, Z., Li, K., Lou, X., & Cui, W. (2020) · Aging · doi:10.18632/aging.103878 · Cited by 12 · see citing works
Dietary fat, telomere length and cognitive function: unravelling the complex relations
Mostafa, H. M. A., Gutiérrez-Tordera, L., Mateu-Fabregat, J., Papandreou, C., & Bulló, M. (2023) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000900 · Cited by 12 · see citing works
Khan, M. A., Haider, N., Singh, T., Bandopadhyay, R., Ghoneim, M. M., Alshehri, S., Taha, M., Ahmad, J., & Mishra, A. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-023-01180-z · Cited by 12 · see citing works
The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases
Papageorgakopoulou, M. A., Bania, A., Lagogianni, I.-A., Birmpas, K., & Assimakopoulou, M. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-03947-6 · Cited by 11 · see citing works
Kreiner, G. (2018) · Pharmacological Reports · doi:10.1016/j.pharep.2018.09.006 · Cited by 9 · see citing works
Robinson, H., Ali, S. I., Díaz‐Hernández, M. E., & Lopez-Gonzalez, R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.874323 · Cited by 7 · see citing works
Mouse models of central nervous system ageing
Heng, Y., Eggen, B. J. L., Boddeke, E., & Kooistra, S. M. (2017) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2018.10.002 · Cited by 8 · see citing works
Self-citationExploring the causal relationship between telomere regulation, aging and neurological disorders
Gupta, G., Ali, H., Singh, S. K., Dua, K., & Jha, S. K. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102930 · Cited by 6 · see citing works
Potential roles of telomeres and telomerase in neurodegenerative diseases
Shao, J., Wang, J., Li, B., & Liu, C. (2024) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2023.41 · Cited by 6 · see citing works
Palomares, D., Vanparys, A., Jorgji, J., Paître, E., Kienlen‐Campard, P., & Suelves, N. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02118-5 · Cited by 7 · see citing works
Carr, L. M., Mustafa, S., Care, A., & Collins‐Praino, L. E. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.04.023 · Cited by 5 · see citing works
Replenishment of Organotypic Hippocampal Slice Cultures with Neonatal or Adult Microglia
Masuch, A., & Biber, K. P. H. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9658-2_10 · Cited by 5 · see citing works
Self-citationChen, X., Huang, Y., Zhao, C., & Huang, M. (2026) · Journal of Neurology · doi:10.1007/s00415-025-13479-1 · Cited by 4 · see citing works
Potential Explanatory Models of the Female Preponderance in Very Late Onset Schizophrenia
Johnstone, S., Cruz, G. A. D., Girard, T., Rajji, T., & Castle, D. J. (2022) · Women · doi:10.3390/women2040033 · Cited by 3 · see citing works
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GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes
MacAulay, N., Alstrom, J. S., Hansen, D. B., & Nielsen, M. S. (2017) · Glia · doi:10.1002/glia.23156 · Cited by 1 · see citing works
lncRNA Glelr modulates microglia inflammatory programs in association with PU.1
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Mechanisms of brain aging. A review: Part I
Berns, S. A., Веремеев, А. В., Lobachev, I. M., Shirshov, A. V., Korshikova, E. A., Timofeev, Y. S., Ринатовна, Г. И., Almazova, I. I., & Drapkina, O. M. (2026) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/10.15829/1728-8800-2026-4986
- Authors
- Scheffold, A., Holtman, I. R., Dieni, S., Brouwer, N., Katz, S.-F., Jebaraj, B. M. C., Kahle, P. J., Hengerer, B., Lechel, A., Stilgenbauer, S., Boddeke, E. W. G. M., Eggen, B. J. L., Rudolph, K.-L., & Biber, K.
- Affiliations
- Universität Ulm (DE)
- University Medical Center Groningen (NL)
- University Medical Center Freiburg (DE)
- Hertie Institute for Clinical Brain Research (DE)
- Boehringer Ingelheim (Germany) (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Corresponding author
- Biber, Knut
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2016-08-22
- Volume
- 4
- Issue
- 1
- Pages
- 87-87
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4994259
- OpenAlex
- W2517605453
- Cited by
- 53
- References
- 89
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 7
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (BI 668/2-2 and BI 668/5-1)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- telomere shortening, Parkinson's disease, alpha-synuclein, synucleinopathies, microglia, microglial activation, alpha-synuclein aggregates, brainstem, motor performance, aging, neurodegeneration
- MeSH terms
- Animals, Brain Stem, Postural Balance, Humans, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Phenotype, RNA, Messenger, Time Factors, Microglia, Disease Progression, Parkinsonian Disorders, alpha-Synuclein, Telomere Shortening, Protein Aggregation, Pathological
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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