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. IMPORTANCEIn 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.

The frequency of yeast [PSI+] prion formation is increased during chronological ageing

“…There is previous evidence to suggest that the increased formation and accumulation of protein aggregates may exert a stimulatory effect on the autophagy pathway. For example, there is a correlation between the accumulation of PrP SC and the enhanced activity of quality control pathways including endoplasmic reticulum chaperones, the unfolded protein response and autophagy 30. In agreement with the idea that enhanced autophagy aids protein homeostasis during ageing, we found reduced levels of amorphous protein aggregation in a [ PSI + ] strain, suggesting that autophagy provides a beneficial effect during chronological ageing by removing potentially harmful protein aggregates, including both amorphous and amyloid forms.…”

The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

“…In several prion models, autophagy is activated through both mTOR and Beclin 1 signaling pathways [88,89], and ALP activators such as rapamycin and trehalose decrease PrP Sc in vitro and in vivo [90,91]. Paradoxically, the antimalarial drug quinacrine, which functions as an autophagy–lysosomal degradation inhibitor, has been shown to have therapeutic effects in prion disease models [92].…”

Axonal changes in experimental prion diseases recapitulate those following constriction of postganglionic branches of the superior cervical ganglion: a comparison 40 years later

“…Data on autophagy in prion diseases and in yeast prions are meagre [21][22][23][24][25][26]. Our initial strategy using the hamster-adapted 263K or 22C-H strains of scrapie [26][27][28][29][30] was subsequently broadened by exploration of human brain biopsies from patients with sporadic CJD, variant CJD, and FFI [31,32]. Experimentally infected animal prion disease models are widely used because of their relatively short incubation periods that, for mice, range from 16 to 18 weeks, and for hamsters from 9 to 10 weeks for the 263K scrapie strain and 24-26 weeks for the 22C-H scrapie strain.…”