Disrupted‐in‐schizophrenia‐1 protects synaptic plasticity in a transgenic mouse model of Alzheimer’s disease as a mitophagy receptor

• Published in: Aging cell Vol. 18; no. 1; pp. e12860 - n/a
• Main Authors: Wang, Zhao‐Tao, Lu, Mei‐Hong, Zhang, Yan, Ji, Wen‐Li, Lei, Lei, Wang, Wang, Fang, Li‐Pao, Wang, Lu‐Wen, Yu, Fan, Wang, Ji, Li, Zhen‐Yu, Wang, Jian‐Rong, Wang, Ting‐Hua, Dou, Fei, Wang, Qin‐Wen, Wang, Xing‐Long, Li, Shao, Ma, Quan‐Hong, Xu, Ru‐Xiang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2019; John Wiley and Sons Inc
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amino Acid Motifs; Amino Acid Sequence; Amyloid beta-Protein Precursor - metabolism; Animals; Autophagosomes - drug effects; Autophagosomes - metabolism; Autophagosomes - ultrastructure; autophagy; Brain; Brain - metabolism; Brain - pathology; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cognition Disorders - complications; Cognition Disorders - physiopathology; Cognitive ability; Dendritic spines; Disc1 protein; Disease Models, Animal; Disrupted‐in‐schizophrenia‐1; Down-Regulation - drug effects; Genetic engineering; HeLa Cells; Humans; Long-term potentiation; Male; Mental disorders; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitophagy; Mitophagy - drug effects; Models, Biological; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Neuronal Plasticity - drug effects; Original; Presenilin 1; Protein Binding - drug effects; Rodents; Schizophrenia; Synaptic plasticity; Toxicity; Transgenic mice; mitophagy; autophagy; Disrupted-in-schizophrenia-1; Alzheimer’s disease; mitochondria
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12860

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted‐in‐schizophrenia‐1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aβ‐treated cultured cells. Disrupted‐in‐schizophrenia‐1 contains a canonical LC3‐interacting region (LIR) motif (210FSFI213), through which DISC1 directly binds to LC3‐I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking‐down of DISC1 blocks Aβ‐induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aβ‐induced mitochondrial dysfunction, loss of spines, suppressed long‐term potentiation (LTP). Overexpression of DISC1 via adeno‐associated virus (serotype 8, AAV8) in the hippocampus of 8‐month‐old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aβ plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aβ accumulation‐induced toxicity through promoting mitophagy.