TY  - JOUR
AU  - Perneel, Jolien
AU  - Lastra Osua, Miranda
AU  - Alidadiani, Sara
AU  - Peeters, Nele
AU  - De Witte, Linus
AU  - Heeman, Bavo
AU  - Manzella, Simona
AU  - De Rycke, Riet
AU  - Brooks, Mieu
AU  - Perkerson, Ralph B
AU  - Calus, Elke
AU  - De Coster, Wouter
AU  - Neumann, Manuela
AU  - Mackenzie, Ian R A
AU  - Van Dam, Debby
AU  - Asselbergh, Bob
AU  - Ellender, Tommas
AU  - Zhou, Xiaolai
AU  - Rademakers, Rosa
TI  - Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health.
JO  - Molecular neurodegeneration
VL  - 20
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2025-00568
SP  - 45
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Mice, Transgenic
KW  - Lysosomes: metabolism
KW  - Mice
KW  - Humans
KW  - Nerve Tissue Proteins: metabolism
KW  - Nerve Tissue Proteins: genetics
KW  - Neurons: metabolism
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Signal Transduction: physiology
KW  - Synapses: metabolism
KW  - Disease Models, Animal
KW  - Lysosomal dysfunction (Other)
KW  - Mouse model (Other)
KW  - Neuronal activity (Other)
KW  - Synaptic signaling (Other)
KW  - TMEM106B (Other)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - TMEM106B protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40269985
C2  - pmc:PMC12016085
DO  - DOI:10.1186/s13024-025-00831-2
UR  - https://pub.dzne.de/record/278077
ER  -