A recent study led by Ludwig-Maximilians-University Munich revealed how mutations in the gene encoding Tectonic β-propeller repeat-containing protein 2 (TECPR2) contribute to the progression of Hereditary Sensory and Autonomic Neuropathy type 9 (HSAN9).
The study, published in Cell Death & Differentiation provides new insights into the molecular mechanisms underlying this fatal neurodevelopmental and neurodegenerative disorder.
HSAN9 affects the sensory and peripheral nervous systems and is caused by homozygous or compound heterozygous mutations in the TECPR2 gene. The protein plays a role in autophagy, but how its deficiency contributes to the development of the disease has remained poorly understood. Christian Behrends and his team generated a Tecpr2 knock-in mouse model carrying the L1139Rfs patient mutation, which results in loss of TECPR2 expression.
Comprehensive phenotyping at the German Mouse Clinic revealed distinct neurobehavioral abnormalities in the mutant mice, including altered gait characterized by reduced temporal and spatial walking parameters and smaller forelimb footprint areas. Gait ataxia and neuropathological features, such as axonal dystrophy, in the mouse model resemble those in HSAN9 patients.
Axonal swelling detected in a specific brain region correlated with neuronal loss and extensive gliosis. Further proteomic and microscopic analyses showed clear functional disturbances in the endolysosomal cell compartment. In addition, transcriptomic analysis of mouse brains revealed increased expression of disease-associated microglia genes, consistent with prominent gliosis. These findings suggest that TECPR2 deficiency impairs the endolysosomal system, affecting not only neurons but also microglia, whose ability to clear neuronal debris appears to be attenuated.
Overall, the neuronal and microglia phenotypes point to a disturbed endolysosomal system when TECPR2 is missing. Dysfunctional neuron–glia interactions may therefore play a critical role in HSAN9-related phenotypes and disease progression in mice and potentially in patients.
Bhattacharya D, da Silva-Buttkus P, Nalbach K, Cheng L, Garrett L, Irmler M, Kislinger G, Werner G, Rodde R, Lengger C, Beckers J, Zimprich A, Hölter SM, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Wefers B, Wurst W, Brill MS, Schifferer M, Lichtenthaler SF, Behrends C. Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia. Cell Death Dis. 2025 Oct 31;16(1):775. doi: 10.1038/s41419-025-08168-w. PMID: 41173829; PMCID: PMC12578842.