Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia

AbstractMitochondria play important roles as the powerhouse of the cell. After cerebral ischemia, mitochondria overproduce reactive oxygen species (ROS), which have been thoroughly studied with the use of superoxide dismutase transgenic or knockout animals. ROS directly damage lipids, proteins, and nucleic acids in the cell. Moreover, ROS activate various molecular signaling pathways. Apoptosis-related signals return to mitochondria, then mitochondria induce cell death through the release of pro-apoptotic proteins such as cytochrome c or apoptosis-inducing factor. Although the mechanisms of cell death after cerebral ischemia remain unclear, mitochondria obviously play a role by activating signaling pathways through ROS production and by regulating mitochondria-dependent apoptosis pathways

Difference between PA700-like proteasome activator complex and the regulatory complex dissociated from the 26S proteasome implies the involvement of modulating factors in the 26S proteasome assembly

AbstractThe PA700-like proteasome activator complex was highly purified from porcine erythrocytes, and its properties were compared with those of the regulatory complex disassembled from the purified 26S proteasome. The molecular mass of the PA700-like complex, which comprises 25–110-kDa subunits, was estimated to be 800 kDa by Superose 6 gel filtration. This complex showed neither ATPase activity nor peptidase activity toward Suc–Leu–Leu–Val–Tyr–MCA. Nevertheless, it was possible to make a high molecular mass complex from the purified PA700-like complex by incubating with the 20S proteasome in the presence of ATP. In contrast, the regulatory complex dissociated from the 26S proteasome did not reconstitute a larger complex under the same conditions. The subunit composition of the PA700-like complex was similar but not identical to that of the regulator complex dissociated from the 26S proteasome: the former complex had a 25-kDa subunit which is absent in the latter, whereas the latter had two or three 43-kDa subunits lacking in the former. These results indicate that the purified PA700-like proteasome activator complex is structurally and functionally distinct from the regulatory complex dissociated from the 26S proteasome, implying the involvement of modulating factors in the 26S proteasome assembly

Genomic copy number variation analysis in multiple system atrophy

Genomic variation includes single-nucleotide variants, small insertions or deletions (indels), and copy number variants (CNVs). CNVs affect gene expression by altering the genome structure and transposable elements within a region. CNVs are greater than 1 kb in size; hence, CNVs can produce more variation than can individual single-nucleotide variations that are detected by next-generation sequencing. Multiple system atrophy (MSA) is an α-synucleinopathy adult-onset disorder. Pathologically, it is characterized by insoluble aggregation of filamentous α-synuclein in brain oligodendrocytes. Generally, MSA is sporadic, although there are rare cases of familial MSA. In addition, the frequencies of the clinical phenotypes differ considerably among countries. Reports indicate that genetic factors play roles in the mechanisms involved in the pathology and onset of MSA. To evaluate the genetic background of this disorder, we attempted to determine whether there are differences in CNVs between patients with MSA and normal control subjects. We found that the number of CNVs on chromosomes 5, 22, and 4 was increased in MSA; 3 CNVs in non-coding regions were considered risk factors for MSA. Our results show that CNVs in non-coding regions influence the expression of genes through transcription-related mechanisms and potentially increase subsequent structural alterations of chromosomes. Therefore, these CNVs likely play roles in the molecular mechanisms underlying MSA

Additional file 2: Figure S1. of Genomic copy number variation analysis in multiple system atrophy

Gel electrophoresis of PCR products for verification analysis. Figure S2. Chromosomal location of CNVs in control subjects. (PPTX 454 kb

Additional file 1: Table S1. of Genomic copy number variation analysis in multiple system atrophy

Number of CNVs in 72 individuals. Table S2. Number of CNVs on autosomal chromosomes in controls and subjects with MSA-C or MSA-P. Table S3. Chromosome numbers at which the 311 CNVs related to MSA were located. Table S4. Details of the 29 CNVs as obtained by cluster analysis. Table S5. Details of the 12 verified CNVs. Table S6. Large CNVs identified in this study. (DOCX 97 kb