New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer's Disease.

Tanja Fuchsberger,Ana Lloret,Jose Viña

doi:10.3390/ijms18051057

Abstract

The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer’s disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

Highlights

The ubiquitin-proteasome system allows dynamic regulation of cell functions by targeting proteins for degradation
Stegmüller et al (2006) reported a mechanism by which the ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C)-Cdh1 controls axonal morphogenesis [13]. They showed that APC/C-Cdh1 operates in the nucleus for inhibition of axonal growth by targeting the transcriptional corepressor Ski-related novel protein N (SnoN) for ubiquitin-dependent proteasomal degradation
It has been reported that APC/C-Cdh1 ubiquitinates cdk5 when it is transported to the cytoplasm, after initiation of the S phase [54]. These findings strongly suggest that APC/C-Cdh1 downregulation is involved in erroneous cell cycle re-entry in Alzheimer’s disease (AD)

Summary

Introduction

The ubiquitin-proteasome system allows dynamic regulation of cell functions by targeting proteins for degradation. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Impaired function of APC/C and accumulation of its substrates have been related to neurodegenerative diseases, as it was shown to be involved in excitotoxicity [21,22], oxidative stress [23], and ectopic cell-cycle re-entry [24,25,26,27].

Results

Conclusion