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.

中文翻译：

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蛋白质 l-异天冬氨酰甲基转移酶缺陷小鼠中与神经退行性疾病和糖尿病肾病相关的 microRNA 的差异表达

蛋白质l-异天冬氨酰甲基转移酶 (PIMT/PCMT1)，一种修复肽和蛋白质中异天冬氨酸残基的酶，由正常l-天冬氨酰和l-天冬氨酸的自发分解产生- 衰老过程中的天冬酰胺残基已被证实与神经退行性疾病 (NDD) 和糖尿病有关。然而，PIMT 功能障碍与这些疾病的假定关联的分子机制尚未阐明。我们的研究旨在鉴定 PIMT 缺陷小鼠大脑和肾脏中差异表达的 microRNA (miRNA)，并揭示 PIMT 相关的 NDD 和糖尿病肾病 (DN) 的表观遗传机制。通过测序差异表达的 miRNA 在 PIMT 敲除 (KO) 小鼠和年龄匹配的野生型 (WT) 同窝仔猪的大脑和肾脏中进行靶点预测和富集分析。序列分析显示 PIMT KO 小鼠大脑中有 40 个差异表达的 miRNA，包括 25 个上调 miRNA 和 15 个下调 miRNA。在 PIMT KO 小鼠肾脏中，有80个差异表达的miRNA，包括40个上调的miRNA和40个下调的miRNA。富集分析和对差异表达 miRNA 的系统文献回顾表明 PIMT 缺乏参与了 NDDs 和 DN 的发病机制。分别在脑、肾和血清来源的外泌体中定量评估了脑和肾之间一些重叠的差异表达 miRNA。尽管是初步的，但这些结果可能有助于研究病理特征并确定 PIMT 功能障碍相关 NDD 和 DN 的潜在治疗靶点和生物标志物。富集分析和对差异表达 miRNA 的系统文献回顾表明 PIMT 缺乏参与了 NDDs 和 DN 的发病机制。分别在脑、肾和血清来源的外泌体中定量评估了脑和肾之间一些重叠的差异表达 miRNA。尽管是初步的，但这些结果可能有助于研究病理特征并确定 PIMT 功能障碍相关 NDD 和 DN 的潜在治疗靶点和生物标志物。富集分析和对差异表达 miRNA 的系统文献回顾表明 PIMT 缺乏参与了 NDDs 和 DN 的发病机制。分别在脑、肾和血清来源的外泌体中定量评估了脑和肾之间一些重叠的差异表达 miRNA。尽管是初步的，但这些结果可能有助于研究病理特征并确定 PIMT 功能障碍相关 NDD 和 DN 的潜在治疗靶点和生物标志物。