Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration

Monika Chauhan,Prashant Kumar Modi,Pushkar Sharma

doi:10.1038/s41419-020-2647-1

Monika Chauhan, Prashant Kumar Modi + Show 1 more

Open Access

https://doi.org/10.1038/s41419-020-2647-1

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Abstract

It is critical for the neuronal cell cycle to remain suppressed in terminally differentiated neurons as its activation results in aberrant cell cycle re-entry that causes neuronal apoptosis (CRNA), which has been observed in several neurodegenerative disorders like Alzheimer’s disease (AD). In the present study, we report that E3 ubiquitin ligase Itch is a major regulator of CRNA and elucidated the mechanism via which it is regulated in this process. Neurotoxic amyloid peptide Aβ42-treated neurons or neurons from an AD transgenic mouse model (TgAD) exhibited aberrant activation of the JNK pathway which resulted in the hyperphosphorylation of Itch. The phosphorylation of Itch primes it for autoubiquitination, which is necessary for its activation. These post-translational modifications of Itch facilitate its interaction with TAp73 resulting in its degradation. These series of events are critical for Itch-mediated CRNA and its phosphorylation and autoubiquitination site mutants reversed this process and were neuroprotective. These studies unravel a novel pathway via which neurodegeneration in AD and possibly other related disorders may be regulated by aberrant regulation of the neuronal cell cycle.

Highlights

It is imperative for the cell cycle of terminally differentiated neurons to remain suppressed in order to maintain their viability
Previous studies performed in non-neuronal HEK293 or HeLa cells indicated that HECT-family ligase Itch is a major mediator of p73 degradation[30]
In order to explore if Itch is involved in TAp73 degradation in neurons in response to Aβ42, cortical neurons were treated with Aβ42 for 48 h as described previously[12] in the presence or absence of siRNA against Itch

Summary

Introduction

It is imperative for the cell cycle of terminally differentiated neurons to remain suppressed in order to maintain their viability. Neurotoxic conditions that include trophic factor withdrawal, encounter with misfolded proteins like beta amyloid peptide Aβ42 and DNA damaging agents are known to trigger aberrant re-entry into the cycle[1,2]. Instead of resulting in mitosis, it causes neuronal cell death[3,4]. One of the key features of CRNA is aberrant regulation of important cell cycle proteins which promote apoptosis. A series of events is triggered by neurotoxic insults resulting in an alarming increase in Cyclin D1 causing activation of CDK4/6, retinoblastoma phosphorylation and transcriptional activation. DNA replication but most of these neurons undergo apoptosis[3,6]. Aberrant cell cycle re-entry and neuronal loss has been observed in several neurodegenerative disorders like Alzheimer’s disease (AD) in which neuronal loss and aberrant cell cycle re-entry are coincidental[7,8,9,10,11]

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