RESUMO
Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.
RESUMO
Neuropilin-1 (NRP-1) is a transmembrane glycoprotein receptor whose distinct sites bind semaphorins and vascular endothelial growth factor family members to mediate the role of these ligands in neuronal axon guidance and angiogenesis, respectively. Similarly, Eph receptors and ephrin ligands play critical roles in various biological functions, and deregulated activation of Eph/ephrin signaling in humans is thought to lead to tumorigenesis. Therefore, in this paper, an attempt was made to elucidate the inhibition potential of nine bioactive compounds from four different native spices of Bangladesh against this couple of receptors via molecular docking study. The molecular docking study was carried out using Vina docking protocol. Finally, the receptor-ligand interaction analysis was carried out using the Discovery Studio Client package. Quercetin and diosgenin of onion showed favorable binding with NRP-1 with low binding energy of -7.8 and -7.2 kcal/mol, respectively, in comparison with the control inhibitor (-6.1 kcal/mol). The study suggests that ligand interaction with the residues Asp 48, Thr 44, Thr 77, Tyr 81, Trp29, Ile 143 of NRP-1 and Lys 653, Phe 765, Ser 763, Thr 699, Ile 683 of Eph might be critical for the inhibitory activity of these receptors. The study provides evidence for consideration of quercetin and diosgenin of onion as valuable small ligand molecules for targeting NRP-1 receptor in treatment and prevention of neurological disorders as well as cancer.