Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease

Impaired phosphorylation of ubiquitin at Ser65 affects OPTN recruitment to mitochondria in prion disease models.

• The PINK1-Parkin-dependent mitophagy pathway is disrupted in prion disease models.
• Diminished OPTN recruitment to mitochondria is linked to reduced phosphorylation of ubiquitin.
• This impairment affects the mitochondrial movement of TBK1 and ATG9A, hindering TBK1 autophosphorylation.
• Reduced TBK1 activity leads to decreased autophagosome formation and defective mitophagy.
• Overexpression of OPTN can mitigate mitophagy impairment and partially restore mitochondrial function.

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