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.

Abstract

Mutations in LRRK2, which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson’s disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer’s disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of β amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2. Using patient-derived cells, brain tissue, and PD model mice, we found that LRRK2 interacted with and phosphorylated APP at Thr668 within its intracellular domain (AICD). Phosphorylation of APP at Thr668 promoted AICD transcriptional activity and correlated with increased nuclear abundance of AICD and decreased abundance of a dopaminergic neuron marker in cultures and brain tissue. The AICD regulates the transcription of genes involved in cytoskeletal dynamics and apoptosis. Overexpression of AICD, but not a phosphodeficient mutant (AICDT668A), increased the loss of dopaminergic neurons in older mice expressing LRRK2G2019S. Moreover, the amount of Thr668-phosphorylated APP was substantially greater in postmortem brain tissue and dopaminergic neurons (generated by reprogramming skin cells) from LRRK2G2019S patients than in those from healthy individuals. LRRK2 inhibitors reduced the phosphorylation of APP at Thr668 in the patient-derived dopaminergic neurons and in the midbrains of LRRK2G2019S mice. Thus, APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD.

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