Antizyme Inhibitor 2-Deficient Mice Exhibit Altered Brain Polyamine Levels and Reduced Locomotor Activity

Abstract

Background: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. Methods: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. β-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the βGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. Results: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. Conclusions: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons.

AZIN1-centric dynamic network biomarker of tipping point in non-small cell lung cancer metastasis

“…Overall, our analysis established that AZIN1 serves as a key regulator of the Module 2 [Figure 3a]. These results are in strong agreement with other studies in which AZIN1 is shown to play an important role in cancer progression through increasing ornithine decarboxylase activity to accelerate the formation of intracellular polyamine [34,35].…”

Bachmann–Bupp syndrome and treatment

“…90 More recently, transgenic mice deficient in AZIN1 and AZIN2 genes have also been developed. [91][92][93] The in vitro and in vivo observations described above provided the scientific basis for our own hypothesis that patients with BABS having a premature stop codon within the C-terminal destabilization domain of ODC may not be able to fully clear ODC protein through the ubiquitin-independent proteasomal degradation pathway. Consequently, we expected to find accumulated ODC protein that remains functionally active, 87 because the Cterminal mutation does not affect the enzyme's activity center.…”

“…SSAT‐1 , AMD1 , SMS , AZ , ARG2 ) have been developed and are summarized in this review 90 . More recently, transgenic mice deficient in AZIN1 and AZIN2 genes have also been developed 91–93 …”

“… 90 More recently, transgenic mice deficient in AZIN1 and AZIN2 genes have also been developed. 91 – 93 …”

Unveiling the hidden players: noncoding RNAs orchestrating polyamine metabolism in disease

“…Moreover, AZIN2 has been found increased in brains affected by Alzheimer’s disease [ 79 , 80 ] and its depletion leads to a reduction in Put levels, which is associated with alterations in motor function. These observations imply a role for AZIN2 in the regulation of dopaminergic neuron function [ 81 ].…”