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

Sci Signal. 2017 Jul 18;10(488):eaam6790. doi: 10.1126/scisignal.aam6790.

Zhong-Can Chen ¹, Wei Zhang ¹, Ling-Ling Chua ², Chou Chai ³, Rong Li ⁴, Lin Lin ⁵ ⁶, Zhen Cao ¹, Dario C Angeles ², Lawrence W Stanton ⁵, Jian-He Peng ⁴, Zhi-Dong Zhou ² ⁷, Kah-Leong Lim ³ ⁷ ⁸, Li Zeng ⁹ ⁷, Eng-King Tan ¹⁰ ⁷ ¹¹

Affiliations

1 Neural Stem Cell Research Laboratory, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
2 Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 169856, Singapore.
3 Neurodegeneration Laboratory, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
4 Analytical Mass Spectrometry Laboratory, Experimental Therapeutics Centre, Agency of Science, Technology and Research (A*STAR), Singapore 138669, Singapore.
5 Stem Cell and Developmental Biology Group, Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore.
6 National University of Singapore (NUS) Graduate School for Integrative Sciences and Engineering, NUS, Singapore 117456, Singapore.
7 Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
8 Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore 117597, Singapore.
9 Neural Stem Cell Research Laboratory, Research Department, National Neuroscience Institute, Singapore 308433, Singapore. li_zeng@nni.com.sg tan.eng.king@sgh.com.sg.
10 Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 169856, Singapore. li_zeng@nni.com.sg tan.eng.king@sgh.com.sg.
11 Department of Neurology, National Neuroscience Institute, SGH Campus, Singapore 169856, Singapore.

PMID: 28720718 DOI: 10.1126/scisignal.aam6790

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 (AICD^T668A), increased the loss of dopaminergic neurons in older mice expressing LRRK2^G2019S Moreover, the amount of Thr⁶⁶⁸-phosphorylated APP was substantially greater in postmortem brain tissue and dopaminergic neurons (generated by reprogramming skin cells) from LRRK2^G2019S 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 LRRK2^G2019S mice. Thus, APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD.

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