Servín-Muñoz Iris Valeria, Ortuño-Sahagún Daniel, Reyes-Mata María Paulina, Griñán-Ferré Christian, Pallàs Mercè, González-Castillo Celia
Laboratorio de Neuroinmunobiología Molecular, Instituto de Neurociencias Translacionales (INT), Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, Guadalajara 44340, Mexico.
Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Mexico.
Genes (Basel). 2025 Jul 24;16(8):865. doi: 10.3390/genes16080865.
BACKGROUND/OBJECTIVES: Niemann-Pick disease Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 100,000 live births that belongs to the lysosomal storage diseases (LSDs). NPC is characterized by the abnormal accumulation of unesterified cholesterol, in addition to being an autosomal recessive inherited pathology, which belongs to LSDs. It occurs in 95% of cases due to mutations in the NPC1 gene, while 5% of cases are due to mutations in the NPC2 gene. In the cerebral cortex (CC), the disease shows lipid inclusions, increased cholesterol and multiple sphingolipids in neuronal membranes, and protein aggregates such as hyperphosphorylated tau, α-Synuclein, TDP-43, and β-amyloid peptide. Mitochondrial damage and oxidative stress are some alterations at the cellular level in NPC. Therefore, the aim of this work was to determine the gene expression profile in the CC of NPC1 mice in order to identify altered molecular pathways that may be related to the pathophysiology of the disease.
In this study, we performed a microarray analysis of a 22,000-gene chip from the cerebral cortex of an NPC mutant mouse compared to a WT mouse. Subsequently, we performed a bioinformatic analysis in which we found groups of dysregulated genes, and their expression was corroborated by qPCR. Finally, we performed Western blotting to determine the expression of proteins probably dysregulated.
We found groups of dysregulated genes in the cerebral cortex of the NPC mouse involved in the ubiquitination, fatty acid metabolism, differentiation and development, and underexpression in genes with mitochondrial functions, which could be involved in intrinsic apoptosis reported in NPC, in addition, we found a generalized deregulation in the cortical circadian rhythm pathway, which could be related to the depressive behavior that has even been reported in NPC patients.
Recognizing that there are changes in the expression of genes related to ubiquitination, mitochondrial functions, and cortical circadian rhythm in the NPC mutant mouse lays the basis for targeting treatments to new potential therapeutic targets.
背景/目的：尼曼-匹克病C型（NPC）是一种常染色体隐性疾病，发病率为1/100000活产儿，属于溶酶体贮积病（LSDs）。NPC的特征是未酯化胆固醇异常蓄积，它是一种常染色体隐性遗传性疾病，属于LSDs。95% 的病例是由NPC1基因突变引起的，而5% 的病例是由NPC2基因突变引起的。在大脑皮层（CC）中，该疾病表现为脂质包涵体、神经元膜中胆固醇和多种鞘脂增加以及蛋白质聚集物，如过度磷酸化的tau蛋白、α-突触核蛋白、TDP-43和β-淀粉样肽。线粒体损伤和氧化应激是NPC细胞水平的一些改变。因此，本研究的目的是确定NPC1小鼠大脑皮层中的基因表达谱，以识别可能与该疾病病理生理学相关的改变的分子途径。
在本研究中，我们对NPC突变小鼠大脑皮层与野生型小鼠大脑皮层进行了22000基因芯片的微阵列分析。随后进行了生物信息学分析，我们发现了失调基因群，并通过qPCR证实了它们的表达。最后进行蛋白质免疫印迹法以确定可能失调的蛋白质的表达。
我们在NPC小鼠大脑皮层中发现了失调基因群，这些基因群参与泛素化、脂肪酸代谢、分化和发育，以及线粒体功能相关基因的表达下调，这可能与NPC中报道的内源性凋亡有关。此外，我们发现皮层昼夜节律通路普遍失调，这可能与NPC患者中甚至报道过的抑郁行为有关。
认识到NPC突变小鼠中与泛素化、线粒体功能和皮层昼夜节律相关的基因表达存在变化，为将治疗靶向新的潜在治疗靶点奠定了基础。
