The APP intracellular domain promotes expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease.

Gain-of-function mutations in the leucine-rich repeat kinase 2 () gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of β-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted expression, thus increasing the abundance of LRRK2 that promotes AICD activation. deficiency in LRRK2 mice suppressed expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased expression and LRRK2-mediated neurotoxicity in LRRK2 mice. In LRRK2 mice or cultured dopaminergic neurons from LRRK2 patients, treatment with itanapraced reduced expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.