Molecular Neurodegeneration (Apr 2025)

Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health

  • Jolien Perneel,
  • Miranda Lastra Osua,
  • Sara Alidadiani,
  • Nele Peeters,
  • Linus De Witte,
  • Bavo Heeman,
  • Simona Manzella,
  • Riet De Rycke,
  • Mieu Brooks,
  • Ralph B. Perkerson,
  • Elke Calus,
  • Wouter De Coster,
  • Manuela Neumann,
  • Ian R. A. Mackenzie,
  • Debby Van Dam,
  • Bob Asselbergh,
  • Tommas Ellender,
  • Xiaolai Zhou,
  • Rosa Rademakers

DOI
https://doi.org/10.1186/s13024-025-00831-2
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 26

Abstract

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Abstract Background 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. Methods 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. Results 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. Conclusion 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. Graphical Abstract

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