Format

Send to

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

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

Author information

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.

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 ╬▓ 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.

PMID:
28720718
DOI:
10.1126/scisignal.aam6790
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center