title: De novo prion aggregates trigger autophagy in skeletal muscle.
abstract: In certain sporadic, familial, and infectious prion diseases, the prion protein misfolds and aggregates in skeletal muscle in addition to the brain and spinal cord. In myocytes, prion aggregates accumulate intracellularly, yet little is known about clearance pathways. Here we investigated the clearance of prion aggregates in muscle of transgenic mice that develop prion disease de novo. In addition to neurodegeneration, aged mice developed a degenerative myopathy, with scattered myocytes containing ubiquitinated, intracellular prion inclusions that were adjacent to myocytes lacking inclusions. Myocytes also showed elevated levels of the endoplasmic reticulum chaperone Grp78/BiP, suggestive of impaired protein degradation and endoplasmic reticulum stress. Additionally, autophagy was induced, as indicated by increased levels of beclin-1 and LC3-II. In C2C12 myoblasts, inhibition of autophagosome maturation or lysosomal degradation led to enhanced prion aggregation, consistent with a role for autophagy in prion aggregate clearance. Taken together, these findings suggest that the induction of autophagy may be a central strategy for prion aggregate clearance in myocytes. IMPORTANCE In prion diseases, the prion protein misfolds and aggregates in the central nervous system and sometimes in other organs, including muscle, yet the cellular pathways of prion aggregate clearance are unclear. Here we investigated the clearance of prion aggregates in the muscle of a transgenic mouse model that develops profound muscle degeneration. We found that endoplasmic reticulum stress pathways were activated and that autophagy was induced. Blocking of autophagic degradation in cell culture models led to an accumulation of aggregated prion protein. Collectively, these findings suggest that autophagy has an instrumental role in prion protein clearance.
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Shivanjali
authors.initials: S
authors.lastname: Joshi-Barr
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Chiang
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.forename: Beata
authors.initials: B
authors.lastname: Sikorska
authors.forename: Pawel
authors.initials: P
authors.lastname: Liberski
authors.forename: Alex
authors.initials: A
authors.lastname: Raeber
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D017096:Prion Diseases / Q000503:physiopathology*
chemical_list: D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse