No abstract

Mutations in the coding sequence of human TECPR2 were recently linked to spastic paraplegia type 49 (SPG49), a hereditary neurodegenerative disorder involving intellectual disability, autonomic-sensory neuropathy, chronic respiratory disease and decreased pain sensitivity. Here, we report the generation of a novel CRISPR-Cas9 tecpr2 knockout (tecpr2 −/− ) mouse that exhibits behavioral pathologies observed in SPG49 patients. tecpr2 −/− mice develop neurodegenerative patterns in an age-dependent manner, manifested predominantly as neuroaxonal dystrophy in the gracile (GrN) and cuneate nuclei (CuN) of the medulla oblongata in the brainstem and dorsal white matter column of the spinal cord. Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome. Taken together, our findings establish the tecpr2 knockout mouse as a potential model for SPG49 and ascribe a new role to TECPR2 in macroautophagy/autophagy-related neurodegenerative disorders.

Autophagy, a conserved membrane trafficking process, sequesters cytoplasmic components into autophagosomes and targets them for lysosomal degradation. The TNF receptor Fn14 participates in multiple intracellular signaling pathways and is strongly induced upon tissue injury and solid tumorigenesis. While Fn14 is a short-lived protein, the regulation of its levels is largely obscure. Here we uncover a role for autophagy in Fn14 turnover, wherein specific core autophagy Atg8 proteins play distinct roles: Fn14 accumulates in the ERGIC in absence of GABARAP but within endosomes in the vicinity of autophagic membranes in absence of GATE-16. Moreover, GABARAP regulates overall cellular levels of Fn14, whereas GATE-16 regulates TWEAK signaling by Fn14 and thereby NF-κB activity. These findings not only implicate different Atg8 proteins in distinct roles within the mechanism of selective autophagic regulation of Fn14, but may also provide a more general view of their role in mediating autophagosome biogenesis from different membrane sources.