PHB2 Alleviates Neurotoxicity of Prion Peptide PrP106-126 via PINK1/Parkin-Dependent Mitophagy

Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP106-126 as a cell model for prion diseases. We examined the role of PHB2 in PrP106-126-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP106-126-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP106-126 induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP106-126-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP106-126, whereas the overexpression of PHB2 alleviated PrP106-126 neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP106-126-treated neurons and protects neurons against the neurotoxicity of the prion peptide.

Automated summary

This study demonstrated the essential role of PHB2 in PINK1/Parkin-mediated mitophagy in PrP106-126-treated neurons, as well as its neuroprotective effect against the neurotoxicity of the prion peptide. PHB2 was found to be involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria, and its depletion worsened neuronal cell death induced by PrP106-126, while its overexpression alleviated PrP106-126 neuronal toxicity.