TECPR2 knock-in mice proteomics

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.