Dataset Information

TECPR2 knock-in mice proteomics

ABSTRACT: Mutation in the gene encoding Tectonic -propeller repeat-containing repeat protein 2 (TECPR2) leads to hereditary sensory and autonomic neuropathy type 9 (HSAN9) which is a fatal complex neurodevelopmental and neurodegenerative disorder involving the sensory and peripheral nervous system. TECPR2 is linked to trafficking and sorting of proteins within the cell, however, its functional role remains poorly defined. Furthermore, molecular insights into pathogenic mechanisms underlying HSAN9 are lacking. Here, we report a mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression. These mice show altered gait, region-specific axonal dystrophy with accumulating membrane-bound structures and extensive gliosis. Transcriptomics, cerebrospinal fluid proteomics and microglia proteome profiling point to damage-associated microglia with a dysfunctional endolysosomal system. The latter was confirmed in cellular assays and linked to TECPR2’s interaction with the membrane-tethering complex HOPS. Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for microglia and neurons.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain, Cell Culture

SUBMITTER: Christian Behrends

LAB HEAD: Christian Behrends

PROVIDER: PXD059099 | Pride | 2025-11-10

REPOSITORIES: Pride

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Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia.

Bhattacharya Debjani D da Silva-Buttkus Patricia P Nalbach Karsten K Cheng Lizhen L Garrett Lillian L Irmler Martin M Kislinger Georg G Werner Georg G Rodde Ramona R Lengger Christoph C Beckers Johannes J Zimprich Annemarie A Hölter Sabine M SM Gailus-Durner Valerie V Fuchs Helmut H Hrabe de Angelis Martin M Wefers Benedikt B Wurst Wolfgang W Brill Monika S MS Schifferer Martina M Lichtenthaler Stefan F SF Behrends Christian C

Cell death & disease 20251031 1

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 ar ...[more]

PMID: 41173829

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