Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease
| Autor: | Zhen Cao, Zhongcan Chen, Lawrence W. Stanton, Zhi Dong Zhou, Eng-King Tan, Chou Chai, Jian-He Peng, Kah-Leong Lim, Ling-Ling Chua, Dario C. Angeles, Li Zeng, Lin Lin, Wei Zhang, Rong Li |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Parkinson's disease Dopamine Mice Transgenic Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Biochemistry Amyloid beta-Protein Precursor Mice 03 medical and health sciences 0302 clinical medicine Degenerative disease Amyloid precursor protein medicine Animals Humans Protein Interaction Domains and Motifs Phosphorylation Molecular Biology Cells Cultured biology Kinase Dopaminergic Neurons Dopaminergic Neurotoxicity Parkinson Disease Cell Biology medicine.disease LRRK2 nervous system diseases Disease Models Animal 030104 developmental biology Mutation biology.protein Cancer research 030217 neurology & neurosurgery |
| Zdroj: | Science Signaling. 10 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aam6790 |
| Popis: | 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 Thr 668 within its intracellular domain (AICD). Phosphorylation of APP at Thr 668 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 Thr 668 -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 Thr 668 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. |
| Databáze: | OpenAIRE |
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