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001     278077
005     20250504001230.0
024 7 _ |a 10.1186/s13024-025-00831-2
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037 _ _ |a DZNE-2025-00568
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Perneel, Jolien
|b 0
245 _ _ |a Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health.
260 _ _ |a London
|c 2025
|b Biomed Central
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520 _ _ |a Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk.To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing.We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals.Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier.
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650 _ 7 |a Lysosomal dysfunction
|2 Other
650 _ 7 |a Mouse model
|2 Other
650 _ 7 |a Neuronal activity
|2 Other
650 _ 7 |a Synaptic signaling
|2 Other
650 _ 7 |a TMEM106B
|2 Other
650 _ 7 |a Membrane Proteins
|2 NLM Chemicals
650 _ 7 |a Nerve Tissue Proteins
|2 NLM Chemicals
650 _ 7 |a TMEM106B protein, human
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Membrane Proteins: metabolism
|2 MeSH
650 _ 2 |a Membrane Proteins: genetics
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Lysosomes: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: metabolism
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: metabolism
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: genetics
|2 MeSH
650 _ 2 |a Signal Transduction: physiology
|2 MeSH
650 _ 2 |a Synapses: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
700 1 _ |a Lastra Osua, Miranda
|b 1
700 1 _ |a Alidadiani, Sara
|b 2
700 1 _ |a Peeters, Nele
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700 1 _ |a De Witte, Linus
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700 1 _ |a Heeman, Bavo
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700 1 _ |a Manzella, Simona
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700 1 _ |a De Rycke, Riet
|b 7
700 1 _ |a Brooks, Mieu
|b 8
700 1 _ |a Perkerson, Ralph B
|b 9
700 1 _ |a Calus, Elke
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700 1 _ |a De Coster, Wouter
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700 1 _ |a Neumann, Manuela
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700 1 _ |a Mackenzie, Ian R A
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700 1 _ |a Van Dam, Debby
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700 1 _ |a Asselbergh, Bob
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700 1 _ |a Ellender, Tommas
|b 16
700 1 _ |a Zhou, Xiaolai
|b 17
700 1 _ |a Rademakers, Rosa
|0 0000-0002-4049-0863
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773 _ _ |a 10.1186/s13024-025-00831-2
|g Vol. 20, no. 1, p. 45
|0 PERI:(DE-600)2244557-2
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|t Molecular neurodegeneration
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|y 2025
|x 1750-1326
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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