Multifaceted Regulation of ALDH1A1 by Cdk5 in Alzheimer ’s Disease Pathogenesis

This study revealed multifaceted regulation of ALDH1A1 by Cdk5 in Alzheimer ’s disease (AD) pathogenesis. ALDH1A1 is a multifunctional enzyme with dehydrogenase, esterase, and anti-oxidant activities. ALDH1A1 is also a major regulator of retinoic acid (RA) signaling, which is critical for normal brain homeostasis. We identified ALDH1A1 as both physiological and pathologic al target of Cdk5. First, under neurotoxic conditions, Cdk5-induced oxidative stress upregulatesALDH1A1 transcription. Second, Cdk5 increases ALDH1A1 levels by preventing its ubiquitylation via direct phosphorylation. Third, ALDH1A1 phosphorylation increases its dehydrogenase activity by altering its tetrameric state to a highly active monomeric state. Fourth, persistent oxidative stress triggered by deregulated Cdk5 inactivates ALDH1A1. Thus, initially, the good Cdk5 attempts to mitigate ensuing oxidative stress by upregulating ALDH1A1 via phosphorylation and paradoxically by increasing oxidative stress. Later, sustained oxidative stress generated by Cdk5 inhibits ALDH1A1 activity, leading to neurotoxicity. ALDH1A1 upregulation is highly neuroprotective. In human AD tissues, ALDH1A1 levels increase with disease severity. However, ALDH1A1 activity was highest at mild and moderate stages, but declines significantly at severe stage. These findings confirm that during the initial stages, neurons attempt to upregulate and activate ALDH1A1 to protect from accruing oxidative stress-induced damage; however, persi...

Source: Molecular Neurobiology - June 8, 2018 Category: Neurology Source Type: research