Differential expression of microRNAs associated with neurodegenerative diseases and diabetic nephropathy in protein l‐isoaspartyl methyltransferase‐deficient mice

Abstract

Protein l‐isoaspartyl methyltransferase (PIMT/PCMT1), an enzyme repairing isoaspartate residues in peptides and proteins that result from the spontaneous decomposition of normal l‐aspartyl and l‐asparaginyl residues during aging, has been revealed to be involved in neurodegenerative diseases (NDDs) and diabetes. However, the molecular mechanisms for a putative association of PIMT dysfunction with these diseases have not been clarified. Our study aimed to identify differentially expressed microRNAs (miRNAs) in the brain and kidneys of PIMT‐deficient mice and uncover the epigenetic mechanism of PIMT‐involved NDDs and diabetic nephropathy (DN). Differentially expressed miRNAs by sequencing underwent target prediction and enrichment analysis in the brain and kidney of PIMT knockout (KO) mice and age‐matched wild‐type (WT) littermates. Sequence analysis revealed 40 differentially expressed miRNAs in the PIMT KO mouse brain including 25 upregulated miRNAs and 15 downregulated miRNAs. In the PIMT KO mouse kidney, there were 80 differentially expressed miRNAs including 40 upregulated miRNAs and 40 downregulated miRNAs. Enrichment analysis and a systematic literature review of differentially expressed miRNAs indicated the involvement of PIMT deficiency in the pathogenesis in NDDs and DN. Some overlapped differentially expressed miRNAs between the brain and kidney were quantitatively assessed in the brain, kidney, and serum‐derived exosomes, respectively. Despite being preliminary, these results may aid in investigating the pathological hallmarks and identify the potential therapeutic targets and biomarkers for PIMT dysfunction‐related NDDs and DN.

Circulating plasma-derived extracellular vesicles expressing bone and kidney markers are associated with neurocognitive impairment in people living with HIV

“…Another study performed by Xia et al (23) showed that EVs and their miRNA cargo derived from patients and rats with injured neurons can target osteoprogenitors to promote osteogenesis, suggesting a neuroimmune crosstalk in the bone-brain axis bone homeostasis. Furthermore, consistent with this notion, a recent study reported that EV miR-34a had the same trend of expression in the brain and the kidney of mice deficient in protein L-isoaspartyl methyltransferase, suggesting that EVs may mediate the exchange of signals in the kidney-brain axis (24). Although our study did not investigate the EV cargo, it is important to mention that circulating EVs, particularly their miRNA content, may shed light on this aspect of interorgan crosstalk and indicate that certain EV cargo may play a role in the neuropathological conditions of tissues, encompassing both in the brain and other organs.…”

The emerging role of exosomes in communication between the periphery and the central nervous system

“…The central nervous system (CNS), which consists of the brain and spinal cord, is responsible for the control and regulation of the physiological and psychological activities of every other system in the body. Recent studies have demonstrated that the peripheral and central immune systems, organs, such as the heart, lung, and kidney, and the brain, can all interact with each other in both healthy and pathological conditions, thus, making the communication between the periphery and the brain a topic of growing interest 1–5 . Evidence has demonstrated that brain disorders can cause issues in peripheral organs 6–8 and vice versa; peripheral pathologies can exacerbate a variety of CNS conditions, including Parkinson's Disease (PD), Alzheimer's Disease (AD), hemorrhagic stroke (HS), ischemic stroke (IS), and traumatic brain injury (TBI) 5,9,10 .…”

“…Recent studies have demonstrated that the peripheral and central immune systems, organs, such as the heart, lung, and kidney, and the brain, can all interact with each other in both healthy and pathological conditions, thus, making the communication between the periphery and the brain a topic of growing interest. 1 , 2 , 3 , 4 , 5 Evidence has demonstrated that brain disorders can cause issues in peripheral organs 6 , 7 , 8 and vice versa; peripheral pathologies can exacerbate a variety of CNS conditions, including Parkinson's Disease (PD), Alzheimer's Disease (AD), hemorrhagic stroke (HS), ischemic stroke (IS), and traumatic brain injury (TBI). 5 , 9 , 10 During the process of interaction between the periphery and CNS, the communicators must play critical roles.…”