Autophagy Contributes to Widespread Neuronal Degeneration in Hamsters Infected with the Echigo-1 Strain of Creutzfeldt-Jakob Disease and Mice Infected with the Fujisaki Strain of Gerstmann-Sträussler-Scheinker (GSS) Syndrome

Abstract

The authors report here robust autophagy observed by electron microscopy in both the Echigo-1 strain of Creutzfeldt-Jakob disease in hamsters and the Fujisaki strain of Gerstmann-Sträussler-Scheinker disease in mice. In both models, autophagic vacuoles were observed in several cellular compartments. In neuronal cell bodies, autophagic vacuoles of different size were seen. The cytoplasm of some neurons also contained semicircular cisterns equivalent to an early autophasophore. The major target of autophagy was dystrophic neurites, i.e., enlarged neuritic processes--mostly dendrites but also axonal terminals and preterminals. They contained numerous double- or multiple-membrane-bound autophagosomes or autophagolysosomes and large multivesicular bodies. Multivesicular bodies were also observed within autophagic vacuoles, and large multivesicular bodies were seen within synaptic terminals. Some dystrophic neurites was filled almost completely with multivesicular bodies; the latter were occasionally confluent. The authors conclude that autophagy is an important part of neuropathology in prion disease. They also suggest that spongiform vacuoles, a hallmark for the whole group of prion diseases, may in reality originate from autophagic vacuoles.

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

“…Multivesicular bodies are frequent in both the Matthews' experiments [46] and in experimental prion diseases described here [28]. In control material they were not very frequent and were of a rather regular form, filled with vesicles with one semicircular enda 'cap' presenting increased electron-density ( Figure 16).…”

“…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.…”

“…For human TSE strains, mice were inoculated either with the Fujisaki (Fukuoka 1) strain of GSS [33,34], and hamsters were inoculated with either the Echigo-1 strain of CJD or the 263K strain of scrapie [28,35]. The Echigo-1 strain of CJD was isolated by Mori and colleagues [35] from a case of 33-year-old female with a panencephalopathic type of GSS [36].…”

“…In control material they were not very frequent and were of a rather regular form, filled with vesicles with one semicircular enda 'cap' presenting increased electron-density ( Figure 16). In prion diseases, MVB accumulated either as round structures (Figures 17-18) or as more elongated forms (Figure 19) [28]. MVBs tend to demonstrate increased density both of inside vesicles and the intravesicular matrix ( Figure 17).…”

Autophagy in axonal and dendritic degeneration

“…Synaptic loss is an early and major feature of the brain pathology induced by prion diseases [58]. Prion infection induced accumulation of autophagosomes within synaptic terminals in various brain regions of infected hamsters and mice [59]. In brain biopsies from the patients with prion diseases, autophagosomes are also found within damaged synapses [27].…”