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000281843 1001_ $$0P:(DE-2719)9003127$$aBhattacharya, Debjani$$b0$$udzne
000281843 245__ $$aNeuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia.
000281843 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2025
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000281843 520__ $$aMutations in the gene encoding Tectonic β-propeller repeat-containing repeat protein 2 (TECPR2) cause hereditary sensory and autonomic neuropathy subtype 9 (HSAN9) which is a fatal neurodevelopmental and neurodegenerative disorder involving the sensory and peripheral nervous system. TECPR2 is ubiquitously expressed and linked to trafficking and sorting within the cell, however, its functional role remains poorly defined. Moreover, molecular insights into pathogenic mechanisms underlying HSAN9 are lacking. Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression. Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis. The affected medulla area prominently features swollen axons filled with amorphous protein aggregates, glycogen granules, single and double membrane vesicles as well as aberrant organelles including ER and mitochondria whose proteome is distinctly altered. Despite the locally restricted pathology the neuronal demise is detectable in the cerebrospinal fluid and responded to by damage-associated microglia. However, their capacity to clear neuronal debris seems attenuated. Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing. This was confirmed in TECPR2 knockout cells and linked to TECPR2's interaction with the homotypic fusion and protein sorting (HOPS)-tethering complex. Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region.
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000281843 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000281843 650_2 $$2MeSH$$aAnimals
000281843 650_2 $$2MeSH$$aMicroglia: metabolism
000281843 650_2 $$2MeSH$$aMicroglia: pathology
000281843 650_2 $$2MeSH$$aNeurons: metabolism
000281843 650_2 $$2MeSH$$aNeurons: pathology
000281843 650_2 $$2MeSH$$aMice
000281843 650_2 $$2MeSH$$aPhenotype
000281843 650_2 $$2MeSH$$aLysosomes: metabolism
000281843 650_2 $$2MeSH$$aGene Knock-In Techniques
000281843 650_2 $$2MeSH$$aEndosomes: metabolism
000281843 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000281843 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000281843 650_2 $$2MeSH$$aDisease Models, Animal
000281843 650_2 $$2MeSH$$aMutation: genetics
000281843 7001_ $$ada Silva-Buttkus, Patricia$$b1
000281843 7001_ $$0P:(DE-2719)9002811$$aNalbach, Karsten$$b2
000281843 7001_ $$0P:(DE-2719)9003128$$aCheng, Lizhen$$b3$$udzne
000281843 7001_ $$aGarrett, Lillian$$b4
000281843 7001_ $$aIrmler, Martin$$b5
000281843 7001_ $$0P:(DE-2719)9000614$$aKislinger, Georg$$b6$$udzne
000281843 7001_ $$0P:(DE-2719)9003459$$aWerner, Georg$$b7$$udzne
000281843 7001_ $$aRodde, Ramona$$b8
000281843 7001_ $$00000-0002-2207-4153$$aLengger, Christoph$$b9
000281843 7001_ $$aBeckers, Johannes$$b10
000281843 7001_ $$aZimprich, Annemarie$$b11
000281843 7001_ $$00000-0003-4878-5241$$aHölter, Sabine M$$b12
000281843 7001_ $$aGailus-Durner, Valerie$$b13
000281843 7001_ $$aFuchs, Helmut$$b14
000281843 7001_ $$0P:(DE-2719)9000920$$aHrabe de Angelis, Martin$$b15
000281843 7001_ $$0P:(DE-2719)2810988$$aWefers, Benedikt$$b16$$udzne
000281843 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b17$$udzne
000281843 7001_ $$0P:(DE-2719)9000978$$aBrill, Monika S$$b18
000281843 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b19$$udzne
000281843 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b20$$udzne
000281843 7001_ $$00000-0002-9184-7607$$aBehrends, Christian$$b21
000281843 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-025-08168-w$$gVol. 16, no. 1, p. 775$$n1$$p775$$tCell death & disease$$v16$$x2041-4889$$y2025
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