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@ARTICLE{Perneel:278077,
      author       = {Perneel, Jolien and Lastra Osua, Miranda and Alidadiani,
                      Sara and Peeters, Nele and De Witte, Linus and Heeman, Bavo
                      and Manzella, Simona and De Rycke, Riet and Brooks, Mieu and
                      Perkerson, Ralph B and Calus, Elke and De Coster, Wouter and
                      Neumann, Manuela and Mackenzie, Ian R A and Van Dam, Debby
                      and Asselbergh, Bob and Ellender, Tommas and Zhou, Xiaolai
                      and Rademakers, Rosa},
      title        = {{I}ncreased {TMEM}106{B} levels lead to lysosomal
                      dysfunction which affects synaptic signaling and neuronal
                      health.},
      journal      = {Molecular neurodegeneration},
      volume       = {20},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-00568},
      pages        = {45},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Animals / Membrane Proteins: metabolism / Membrane
                      Proteins: genetics / Mice, Transgenic / Lysosomes:
                      metabolism / Mice / Humans / Nerve Tissue Proteins:
                      metabolism / Nerve Tissue Proteins: genetics / Neurons:
                      metabolism / Neurodegenerative Diseases: metabolism /
                      Neurodegenerative Diseases: genetics / Signal Transduction:
                      physiology / Synapses: metabolism / Disease Models, Animal /
                      Lysosomal dysfunction (Other) / Mouse model (Other) /
                      Neuronal activity (Other) / Synaptic signaling (Other) /
                      TMEM106B (Other) / Membrane Proteins (NLM Chemicals) / Nerve
                      Tissue Proteins (NLM Chemicals) / TMEM106B protein, human
                      (NLM Chemicals)},
      cin          = {AG Neumann},
      ddc          = {570},
      cid          = {I:(DE-2719)1210003},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40269985},
      pmc          = {pmc:PMC12016085},
      doi          = {10.1186/s13024-025-00831-2},
      url          = {https://pub.dzne.de/record/278077},
}