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000278077 037__ $$aDZNE-2025-00568
000278077 041__ $$aEnglish
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000278077 1001_ $$aPerneel, Jolien$$b0
000278077 245__ $$aIncreased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health.
000278077 260__ $$aLondon$$bBiomed Central$$c2025
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000278077 520__ $$aGenetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk.To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing.We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals.Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier.
000278077 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000278077 650_7 $$2Other$$aLysosomal dysfunction
000278077 650_7 $$2Other$$aMouse model
000278077 650_7 $$2Other$$aNeuronal activity
000278077 650_7 $$2Other$$aSynaptic signaling
000278077 650_7 $$2Other$$aTMEM106B
000278077 650_7 $$2NLM Chemicals$$aMembrane Proteins
000278077 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000278077 650_7 $$2NLM Chemicals$$aTMEM106B protein, human
000278077 650_2 $$2MeSH$$aAnimals
000278077 650_2 $$2MeSH$$aMembrane Proteins: metabolism
000278077 650_2 $$2MeSH$$aMembrane Proteins: genetics
000278077 650_2 $$2MeSH$$aMice, Transgenic
000278077 650_2 $$2MeSH$$aLysosomes: metabolism
000278077 650_2 $$2MeSH$$aMice
000278077 650_2 $$2MeSH$$aHumans
000278077 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000278077 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000278077 650_2 $$2MeSH$$aNeurons: metabolism
000278077 650_2 $$2MeSH$$aNeurodegenerative Diseases: metabolism
000278077 650_2 $$2MeSH$$aNeurodegenerative Diseases: genetics
000278077 650_2 $$2MeSH$$aSignal Transduction: physiology
000278077 650_2 $$2MeSH$$aSynapses: metabolism
000278077 650_2 $$2MeSH$$aDisease Models, Animal
000278077 7001_ $$aLastra Osua, Miranda$$b1
000278077 7001_ $$aAlidadiani, Sara$$b2
000278077 7001_ $$aPeeters, Nele$$b3
000278077 7001_ $$aDe Witte, Linus$$b4
000278077 7001_ $$aHeeman, Bavo$$b5
000278077 7001_ $$aManzella, Simona$$b6
000278077 7001_ $$aDe Rycke, Riet$$b7
000278077 7001_ $$aBrooks, Mieu$$b8
000278077 7001_ $$aPerkerson, Ralph B$$b9
000278077 7001_ $$aCalus, Elke$$b10
000278077 7001_ $$aDe Coster, Wouter$$b11
000278077 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b12$$udzne
000278077 7001_ $$aMackenzie, Ian R A$$b13
000278077 7001_ $$aVan Dam, Debby$$b14
000278077 7001_ $$aAsselbergh, Bob$$b15
000278077 7001_ $$aEllender, Tommas$$b16
000278077 7001_ $$aZhou, Xiaolai$$b17
000278077 7001_ $$00000-0002-4049-0863$$aRademakers, Rosa$$b18
000278077 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-025-00831-2$$gVol. 20, no. 1, p. 45$$n1$$p45$$tMolecular neurodegeneration$$v20$$x1750-1326$$y2025
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