Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid β-induced neuronal damage

Abstract

MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells. MDMx is also expressed in postmitotic neurons, with prosurvival roles that are independent of its extensively described roles in carcinogenesis. We and others have shown a role for MDMx loss in neuronal death in vitro and in vivo in several neurodegenerative diseases. Further, we have recently shown that MDMx is targeted for proteolytic degradation by calcium-dependent proteases, calpains, in neurons in vitro, and that MDMx overexpression provided partial neuroprotection in a model of HIV-associated neurodegeneration. Here, we assessed whether amyloid β (Aβ)-induced MDMx degradation occurred in Alzheimer’s Disease (AD) models. Our data shows an age-dependent reduction in MDMx levels in cholinergic neurons within the cortex of adult mice expressing the swedish mutant of the amyloid precursor protein, APP in the Tg2576 murine model of AD. In vitro, Aβ treatment of primary cortical neurons led to the caspase-dependent MDMx degradation. Our findings suggest that MDMx degradation associated with neuronal death occurs via caspase activation in neurons, and that the progressive loss of MDMx protein represents a potential mechanism of Aβ-induced neuronal death during disease progression in AD.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Therefore, MDMX overexpression in RA contributes to the hyperplastic phenotype of this disease, and MDMX inhibitors may be useful for treating RA. Moreover, Colacurcio et al examined the expression and roles of MDMX in AD models. They observed that MDMX is degraded in a caspase‐dependent manner in Aβ‐treated primary cortical neurons .…”

“…Moreover, Colacurcio et al examined the expression and roles of MDMX in AD models. They observed that MDMX is degraded in a caspase‐dependent manner in Aβ‐treated primary cortical neurons . The MDMX expression level was also reduced in the Tg2576 murine model of AD in an age‐dependent manner .…”

“…They observed that MDMX is degraded in a caspase‐dependent manner in Aβ‐treated primary cortical neurons . The MDMX expression level was also reduced in the Tg2576 murine model of AD in an age‐dependent manner . In obesity, Kon et al also observed that a HFD could not induce fat accumulation in p53 3KR/3KR /MDMX −/− mice, which implies that MDMX may not play a critical role in p53 protein degradation under those circumstances .…”

FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity

“…We also demonstrated that caspase 8 binds to both FBXO7 and FOXO4. Although protease-dependent protein degradation is a minor pathway, several proteins have been identified as targets of the caspase-dependent pathway ( 48 , 49 ). No known target has been reported as substrate(s) of caspase 8, except for cIAP-1.…”