Figure 3.

Loss of PrP^C control of β1 integrin–ROCK signaling upon prion infection alters neuronal polarity, renders neurons highly sensitive to TNFα, and promotes PrP^Sc and Aβ accumulation. (A) In prion-infected neurons, PrP^Sc provokes a loss of PrP^C negative regulatory role on β1 integrin/ROCK signaling. Overactivated ROCKs (i) affect the neuronal polarity and connectivity via the LIMK/cofilin/actin pathway, (ii) favor plasma membrane TNFR accumulation, and (iii) amplify the production of PrP^Sc and Aβ via PDK1 overactivation and TACE internalization. (B) In the brain, prion-infected glial cells release neurotoxic factors such as TNFα that would precipitate the death of prion-infected neurons primed by the ROCK-dependent accumulation of TNFR1 at the plasma membrane. The ROCK-dependent rise of PrP^Sc and Aβ peptides would self-sustain the toxic dialog between microglial cells and neurons (microglial reaction).