Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

Embryonic muscle development and fibre type differentiation has always been a topic of great importance due to its impact on both human health and farm animal financial values. Myozenin3 (Myoz3) is an important candidate gene that may regulate these processes. In the current study, we knocked down and overexpressed Myoz3 in chicken embryonic fibroblasts (CEFs) and chicken myoblasts, then utilized RNA-seq technology to screen genes, pathways and biological processes associated with Myoz3. Multiple differentially expressed genes were identified, including MYH10, MYLK2, NFAM1, MYL4, MYL9, PDZLIM1; those can in turn regulate each other and influence the development of muscle fibres. Gene ontology (GO) terms including some involved in positive regulation of cell proliferation were enriched. We further validated our results by testing the activity of cells by cell counting kit-8(CCK-8) and confirmed that under the condition of Myoz3 overexpression, the proliferation rate of CEFs and myoblasts was significantly upregulated, in addition, expression level of fast muscle specific gene was also significantly upregulated in myoblasts. Pathway enrichment analysis revealed that the PPAR (Peroxisome Proliferator-Activated Receptor) pathway was enriched, suggesting the possibility that Myoz3 regulates muscle fibre development and differentiation through the PPAR pathway. Our results provide valuable evidence regarding the regulatory functions of Myoz3 in embryonic cells by screening multiple candidate genes, biological processes and pathways associated with Myoz3.

Previous studies reported that the Myoz1 gene plays a crucial role in signal transduction and muscle fibre type differentiation. This finding suggests that the Myoz1 gene is a potential candidate for affecting carcase and meat quality traits in animals. Therefore, this study aimed to detect genetic variations in Avian and Yellow Bantam chickens and to evaluate the effects of these variations on economically important carcase and meat-quality traits. Expression analysis using quantitative real-time PCR indicated that Myoz1 was broadly expressed in all four studied tissues (liver, heart, breast muscle and leg muscle). Expression of Myoz1 was significantly higher in both leg muscle and breast muscle compared to the liver and heart. Then, using direct sequencing, a total of five single nucleotide polymorphisms (SNPs) were identified within the Myoz1 gene in two breeds of chickens. These breeds included three non-synonymous SNPs (SNP1: g. 16022512 G > T, SNP3: g. 16022560 C > T and SNP5: g.16023903 A > G) corresponding to A103S, H119Y and S189G, respectively. Statistical analyses indicated that SNP2 (g. 16022529 T > C), SNP3, SNP4 (g.16023878 A > C) and SNP5 significantly influenced some carcase and meat quality traits. Meanwhile, we did not find any association between the constructed haplotype and carcase traits in the Avian nor Yellow Bantam chickens. In conclusion, SNPs in the Myoz1 gene could be used for marker-assisted selection in chicken breeding. ARTICLE HISTORY

Myozenin3 (Myoz3) has been reported to bind multiple Z-disc proteins and hence play a key role in signal transduction and muscle fiber type differentiation. The purpose of current study is to better understand the basic characteristics of Myoz3. Firstly, we cloned the ORF (open reading frame) of the Myoz3 gene. AA (amino acid) sequence analysis revealed that the Myoz3 gene encodes a 26 kDa protein which have 97% identities with that of turkey. Expression profiling showed that Myoz3 mRNA is mainly expressed in leg muscle and breast muscle. Furthermore, we investigated Myoz3 gene polymorphisms in two broiler breeds, the Yellow Bantam (YB) and the Avian. Five SNPs (single nucleotide polymorphisms) were identified in the YB breed and 3 were identified in the Avian breed. Genotypes and haplotype were constructed and their associations with carcass traits were analyzed. In the YB breed, c.516 C>T had a strong effect on both shank bone length and the L⁎ value of breast muscle, and the H1H3 diplotype had the highest FC compared to other diplotypes. The markers identified in this study may serve as useful targets for the marker-assisted selection (MAS) of growth and meat quality traits in chickens.

The ubiquitin E3 ligase RNF220 and its co-factor ZC4H2 are required for multiple neural developmental processes through different targets, including spinal cord patterning and the development of the cerebellum and the locus coeruleus. Here, we explored the effects of loss of ZC4H2 and RNF220 on the proliferation and differentiation of neural stem cells (NSCs) derived from mouse embryonic cortex. We showed that loss of either ZC4H2 or RNF220 inhibits the proliferation and promotes the differentiation abilities of NSCs in vitro. RNA-Seq profiling revealed 132 and 433 differentially expressed genes in the ZC4H2−/− and RNF220−/− NSCs, compared to wild type (WT) NSCs, respectively. Specifically, Cend1, a key regulator of cell cycle exit and differentiation of neuronal precursors, was found to be upregulated in both ZC4H2−/− and RNF220−/− NSCs at the mRNA and protein levels. The targets of Cend1, such as CyclinD1, Notch1 and Hes1, were downregulated both in ZC4H2−/− and RNF220−/− NSCs, whereas p53 and p21 were elevated. ZC4H2−/− and RNF220−/− NSCs showed G0/G1 phase arrest compared to WT NSCs in cell cycle analysis. These results suggested that ZC4H2 and RNF220 are likely involved in the regulation of neural stem cell proliferation and differentiation through Cend1.

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