Research ArticleNeurodegeneration

Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease

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Sci. Signal.  18 Jul 2017:
Vol. 10, Issue 488, eaam6790
DOI: 10.1126/scisignal.aam6790

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The amyloid connection in Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by motor control impairments and, eventually, dementia due to the loss of dopaminergic neurons in the brain. Activating mutations in the kinase LRRK2 are among the most common genetic associations with the disease. Chen et al. discovered why activating LRRK2 mutations are toxic to neurons. Mutant LRRK2 phosphorylated amyloid precursor protein (APP) at a residue within a cleaved region called the APP intracellular domain (AICD). Analysis of a mouse model, patient-derived neurons, and postmortem brain tissue suggests that phosphorylation of APP increases its nuclear translocation and transcriptional activity, leading to the loss of dopaminergic neurons. Inhibiting LRRK2 or blocking APP cleavage might be therapeutic in patients. The findings also connect the pathologies of PD and Alzheimer’s disease, in which dementia is commonly associated with the production of another cleavage product of APP, amyloid-β.