Insights into the Evolutionary Features of Human Neurodegenerative Diseases

Bioinformatics Centre, Bose Institute, Kolkata, India.
PLoS ONE (Impact Factor: 3.23). 10/2012; 7(10):e48336. DOI: 10.1371/journal.pone.0048336
Source: PubMed


Comparative analyses between human disease and non-disease genes are of great interest in understanding human disease gene evolution. However, the progression of neurodegenerative diseases (NDD) involving amyloid formation in specific brain regions is still unknown. Therefore, in this study, we mainly focused our analysis on the evolutionary features of human NDD genes with respect to non-disease genes. Here, we observed that human NDD genes are evolutionarily conserved relative to non-disease genes. To elucidate the conserved nature of NDD genes, we incorporated the evolutionary attributes like gene expression level, number of regulatory miRNAs, protein connectivity, intrinsic disorder content and relative aggregation propensity in our analysis. Our studies demonstrate that NDD genes have higher gene expression levels in favor of their lower evolutionary rates. Additionally, we observed that NDD genes have higher number of different regulatory miRNAs target sites and also have higher interaction partners than the non-disease genes. Moreover, miRNA targeted genes are known to have higher disorder content. In contrast, our analysis exclusively established that NDD genes have lower disorder content. In favor of our analysis, we found that NDD gene encoded proteins are enriched with multi interface hubs (party hubs) with lower disorder contents. Since, proteins with higher disorder content need to adapt special structure to reduce their aggregation propensity, NDD proteins found to have elevated relative aggregation propensity (RAP) in support of their lower disorder content. Finally, our categorical regression analysis confirmed the underlined relative dominance of protein connectivity, 3'UTR length, RAP, nature of hubs (singlish/multi interface) and disorder content for such evolutionary rates variation between human NDD genes and non-disease genes.

Download full-text


Available from: Tina Begum, Nov 22, 2014
26 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microbes have adapted efficient mechanisms to contend with environmental changes. The emergence of oxygen was a major event that led to an abrupt change in Earth's atmosphere. To adjust with this shift in environmental condition ancient microbes must have undergone several modifications. Although some proteomic and genomic attributes were proposed to facilitate survival of microorganisms in the presence of oxygen, the process of adaptation still remains elusive. Recent studies have focused that intrinsically disordered proteins play crucial roles in adaptation to a wide range of ecological conditions. Therefore, it is likely that disordered proteins could also play indispensable roles in microbial adaptation to the aerobic environment. To test this hypothesis we measured the disorder content of 679 prokaryotes from four oxygen requirement groups. Our result revealed that aerobic proteomes are endowed with the highest protein disorder followed by facultative microbes. Minimal disorder was observed in anaerobic and microaerophilic microbes with no significant difference in their disorder content. Considering all the potential confounding factors that can modulate protein disorder, here we established that the high protein disorder in aerobic microbe is not a by-product of adaptation to any other selective pressure. On the functional level, we found that the high disorder in aerobic proteomes has been utilized for processes that are important for their aerobic lifestyle. Moreover, aerobic proteomes were found to be enriched with disordered binding sites and to contain transcription factors with high disorder propensity. Based on our results, here we proposed that the high protein disorder is an adaptive opportunity for aerobic microbes to fit with the genomic and functional complexities of the aerobic lifestyle.
    Gene 07/2014; 548(1). DOI:10.1016/j.gene.2014.07.002 · 2.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: The aim of the present study was to investigate the impact of different stroke subtypes on the glymphatic system using MRI. Methods: We first improved and characterized an in vivo protocol to measure the perfusion of the glymphatic system using MRI after minimally invasive injection of a gadolinium chelate within the cisterna magna. Then, the integrity of the glymphatic system was evaluated in 4 stroke models in mice including subarachnoid hemorrhage (SAH), intracerebral hemorrhage, carotid ligature, and embolic ischemic stroke. Results: We were able to reliably evaluate the glymphatic system function using MRI. Moreover, we provided evidence that the glymphatic system was severely impaired after SAH and in the acute phase of ischemic stroke, but was not altered after carotid ligature or in case of intracerebral hemorrhage. Notably, this alteration in glymphatic perfusion reduced brain clearance rate of low-molecular-weight compounds. Interestingly, glymphatic perfusion after SAH can be improved by intracerebroventricular injection of tissue-type plasminogen activator. Moreover, spontaneous arterial recanalization was associated with restoration of the glymphatic function after embolic ischemic stroke. Conclusions: SAH and acute ischemic stroke significantly impair the glymphatic system perfusion. In these contexts, injection of tissue-type plasminogen activator either intracerebroventricularly to clear perivascular spaces (for SAH) or intravenously to restore arterial patency (for ischemic stroke) may improve glymphatic function.
    Stroke 09/2014; 45(10). DOI:10.1161/STROKEAHA.114.006617 · 5.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: At the emergence of endothermic vertebrates, GC rich regions of the ectothermic ancestral genomes underwent a significant GC increase. Such an increase was previously postulated to increase thermodynamic and structural stability of proteins through selective increase of protein hydrophobicity. Here, we found that, increase in GC content promotes a higher content of disorder promoting amino acid in endothermic vertebrates proteins and that the increase in hydrophobicity is mainly due to a higher content of the small disorder promoting amino acid alanine. In endothermic vertebrates, prevalence of disordered residues was found to promote functional diversity of proteins encoded by GC rich genes. Higher fraction of disordered residues in this group of proteins was also found to minimize their aggregation tendency. Thus, we propose that the GC transition has favored disordered residues to promote functional diversity in GC rich genes, and to protect them against functional loss by protein misfolding.
    Genomics 09/2014; 104(6). DOI:10.1016/j.ygeno.2014.09.003 · 2.28 Impact Factor
Show more