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@ARTICLE{Bhattacharya:281843,
      author       = {Bhattacharya, Debjani and da Silva-Buttkus, Patricia and
                      Nalbach, Karsten and Cheng, Lizhen and Garrett, Lillian and
                      Irmler, Martin and Kislinger, Georg and Werner, Georg and
                      Rodde, Ramona and Lengger, Christoph and Beckers, Johannes
                      and Zimprich, Annemarie and Hölter, Sabine M and
                      Gailus-Durner, Valerie and Fuchs, Helmut and Hrabe de
                      Angelis, Martin and Wefers, Benedikt and Wurst, Wolfgang and
                      Brill, Monika S and Schifferer, Martina and Lichtenthaler,
                      Stefan F and Behrends, Christian},
      title        = {{N}europathy-associated {T}ecpr2 mutation knock-in mice
                      reveal endolysosomal loss of function phenotypes in neurons
                      and microglia.},
      journal      = {Cell death $\&$ disease},
      volume       = {16},
      number       = {1},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DZNE-2025-01222},
      pages        = {775},
      year         = {2025},
      abstract     = {Mutations in the gene encoding Tectonic β-propeller
                      repeat-containing repeat protein 2 (TECPR2) cause hereditary
                      sensory and autonomic neuropathy subtype 9 (HSAN9) which is
                      a fatal neurodevelopmental and neurodegenerative disorder
                      involving the sensory and peripheral nervous system. TECPR2
                      is ubiquitously expressed and linked to trafficking and
                      sorting within the cell, however, its functional role
                      remains poorly defined. Moreover, molecular insights into
                      pathogenic mechanisms underlying HSAN9 are lacking. Here, we
                      report a novel mouse model which harbors a HSAN9-associated
                      nonsense mutation that causes loss of TECPR2 expression.
                      Mice show altered gait, highly region-specific axonal
                      dystrophy, and extensive local gliosis. The affected medulla
                      area prominently features swollen axons filled with
                      amorphous protein aggregates, glycogen granules, single and
                      double membrane vesicles as well as aberrant organelles
                      including ER and mitochondria whose proteome is distinctly
                      altered. Despite the locally restricted pathology the
                      neuronal demise is detectable in the cerebrospinal fluid and
                      responded to by damage-associated microglia. However, their
                      capacity to clear neuronal debris seems attenuated. Overall,
                      neuronal and microglia phenotypes point to a dysfunctional
                      endolysosomal system when TECPR2 is missing. This was
                      confirmed in TECPR2 knockout cells and linked to TECPR2's
                      interaction with the homotypic fusion and protein sorting
                      (HOPS)-tethering complex. Collectively, we uncovered a role
                      of TECPR2 in endolysosome maintenance which seems relevant
                      for healthy neurons in a particular brain region.},
      keywords     = {Animals / Microglia: metabolism / Microglia: pathology /
                      Neurons: metabolism / Neurons: pathology / Mice / Phenotype
                      / Lysosomes: metabolism / Gene Knock-In Techniques /
                      Endosomes: metabolism / Nerve Tissue Proteins: genetics /
                      Nerve Tissue Proteins: metabolism / Disease Models, Animal /
                      Mutation: genetics / Nerve Tissue Proteins (NLM Chemicals)},
      cin          = {AG Lichtenthaler / AG Wurst / AG Misgeld},
      ddc          = {570},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)1140001 /
                      I:(DE-2719)1110000-4},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41173829},
      pmc          = {pmc:PMC12578842},
      doi          = {10.1038/s41419-025-08168-w},
      url          = {https://pub.dzne.de/record/281843},
}