LAUSR

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) 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 LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 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 LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 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. Description A feed-forward loop between an APP fragment and the kinase LRRK2 promotes Parkinson’s disease pathology. Spiraling into neurodegeneration Activating mutations in the kinase LRRK2 cause Parkinson’s disease (PD) in some patients. Mutant LRRK2 can promote the processing of APP into its transcriptionally active form, the APP intracellular domain (AICD). Zhang et al. showed that these proteins are linked in a self-perpetuating cycle. In cultured neurons and brain tissue from mouse models of PD, LRRK2-mediated phosphorylation of APP increased the abundance and activity of the AICD that then directly mediated LRRK2 transcription. Pathological markers in LRRK2-mutant PD models were reduced by targeting the AICD with itanapraced, a small-molecule inhibitor that is currently in trials to treat Alzheimer’s disease. The findings reveal that LRRK2 and the AICD are reciprocally linked and that itanapraced may be therapeutically beneficial in PD.