Carboxypeptidase E/Neurotrophic factor-α1 is a novel neuroprotective protein functioning independently of its prohormone processing enzymatic activity

Authors

• L Xiao
• X Yang
• VK SHARMA
• D ABEBE
• A PELTEKIAN
• YP LOH

Abstract

Carboxypeptidase E (CPE) also known as Neurotrophic factor-α1 (NF-α1), was first identified as an exopeptidase and is highly expressed in the nervous and endocrine systems. It functions intracellularly as a prohormone/proneuropeptide processing enzyme. Recent studies show that CPE/ NF-α1 plays a critical role extracellularly, as a trophic factor to mediate neuroprotection, stem cell differentiation and neurite outgrowth in vitro. To show that these neurological functions are independent of its enzymatic activity, we generated a CPE/NF-α1 knockout (CPE-KO) and a mouse model with a CPE E342Q point mutation which obliterates the enzymatic activity. We found that both CPE-KO and E342Q mice exhibited increased body weight and glucose levels due to lack of processing of prohormones and neuropeptides to yield insulin and peptides that affect feeding. Brain morphology studies by Nissl staining revealed that the CPE-KO mice had significant degeneration of CA3 regions of hippocampus, while E342Q mice had an intact hippocampus, similar to wild-type (WT) animals. In addition, doublecortin positive cells (neuroblast marker) in CPE-KO mice were significantly decreased in dentate gyrus, but there was no difference between E342Q and WT mice. Microtubule-associated protein 2 staining showed degeneration of dendrites in the hippocampal CA3 region in CPE-KO mice, but there was no difference between E342Q and WT mice. To investigate the effect of E342Q mutation on various behaviors, open field, forced-swim test, and Morris water maze tests were performed on the mice. The results showed that WT and E342Q mice exhibited a gradual decrease in escape latency during the 5-day training in the Morris water maze test, while CPE-KO mice demonstrated an abnormal acquisition curve. In probe test, both WT and E342Q mice spent twice as much time in the target quadrant than other quadrants, unlike the CPE-KO mice. These results suggest E342Q mutant mice maintain normal learning and cognitive ability despite the loss of CPE enzymatic function; in contrast learning and memory function were compromised in CPE KO mice. This study provides in vivo evidence that CPE/NF-α1 is a novel trophic factor that functions in neuroprotection, independent of its enzymatic role in prohormone processing.

Scientific Focus Area: Neuroscience

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