Staufen blocks autophagy in neurodegeneration

Abstract

AbstractResponse to cellular stress represents a highly conserved pathway in evolution. Cells respond to stress with modified synthesis of new proteins by the formation of stress granules (SGs), inhibition of translation initiation and by increased recycling of cellular components through autophagy. One of the master regulators of this response is the mechanistic target of rapamycin (mTOR) kinase1,2. We recently reported that Staufen1 (STAU1), a stress granule protein, was overabundant in the rare neurodegenerative disorder SCA2 and provided a link between SG formation and autophagy3. In cells harboring mutant ATXN2, STAU1 could also be increased by bafilomycin A consistent with impaired autophagosome lysosome fusion3. Here we now examine this association and show the molecular mechanism leading to autophagic block in cells with microtubule associated protein tau (MAPT), presenilin 1 (PSEN1), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP) or C9orf72-SMCR8 complex subunit (C9orf72) mutations underlying a great number of neurodegenerative diseases4–8. We found that STAU1 overabundance was present in all cell lines and animal models tested, that it was post-translational, and that it was associated with an increase in phosphorylated mTOR (P-mTOR) and autophagic block. Exogenous expression of STAU1 in wild-type cells was sufficient to reduce autophagic flux by itself. Mechanistically, STAU1 directly interacted with the mTOR-5’UTR and enhanced mTOR translation. As STAU1 itself is degraded by autophagy, this interaction and the resulting autophagic block results in a maladaptive amplifying response to chronic stress. Targeting STAU1 by RNAi decreased mTOR hyperactivity and normalized mTOR downstream targets in dividing cells, post-mitotic neurons and animal models of SCA2 and ALS-TDP-43 or C9orf72 associated neurodegeneration. In summary, STAU1 is necessary and sufficient to mediate a maladaptive cellular stress response and is a novel target for RNAi-mediated treatment of neurodegenerative diseases.