DISC1 Improves Cognitive Deficits In A Transgenic Mouse Model Of Alzheimer’s Disease As A Mitophagy Receptor

Alzheimer’s disease(AD),one of the most common neurodegenerative diseases,is characterized by amyloid plaques formed by accumulation of amyloid-β(Aβ)and neurofibrillary tangles formed by hyperphosphorylated tau.In addition,mitochondrial abnormalities have been observed in the brains of AD patients,which is even prior to the onset of histopathological or clinical features.Accumulation of impaired mitochondria leads to neuronal degeneration in Alzheimer’s disease.Therefore,studying how to eliminate the damaged mitochondria in the brain of patients with Alzheimer’s disease and its specific molecular mechanism may further reveal the pathogenesis of Alzheimer’s disease,so as to find a new way for the treatment of Alzheimer’s disease.Mitophagy,a selective autophagy for the removal of dysfunctional mitochondria,is a key pathway in mitochondrial quality control.The damaged mitochondria is selectively gulfed into autophagosomes and subsequently degraded within lysosomes which is fused with autophagosomes.Mitophagy is comprised in AD,which contributes to mitochondrial dysfunction in AD.Disrupted-in-schizophrenia-1(DISCI),is a genetic risk factor for various psychiatric disorders including schizophrenia,major depression and bipolar disorders.Recent studies indicate a close link of DISC1 to AD.We show levels of Disrupted-in-schizophrenia-1(DISCI),which is genetically associated with psychiatric disorders and AD,decrease in the brains of AD patients and transgenic model mice and upon Aβ treatment in cultured cells.DISCI contains a canonical LC3-interacting region(LIR)motif(210FSFI213),through which DISCI directly binds to LC3-I/II.Overexpression of DISCI enhances mitophagy through its binding to LC3,whereas knocking-down of DISCI blocks Aβ-induced mitophagy.We further observe overexpression of DISCI,but not its mutant(muFSFI)which abolishes the interaction of DISCI 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 DISCI with LC3.In conclusion,these results indicate that DISCI is a novel mitophagy receptor,which impoves to protects neuros from Aβ accumulation induced toxicity through promoting mitophagy.