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Wednesday, October 2, 2019

Rab7a and CMT2b Essay -- Biology, Proteins, Cells

Rab7a and Charcot-Marie-Tooth Disease Type 2b The aim of this essay is to review recent research into the Rab7a gene mutations and the mechanistic causes of Charcot Marie Tooth disease type 2b. It will ascertain if there is a clear forerunner in terms of theory of pathology due to Rab7a mutations. Any specific potential treatments for CMT2b that have been discovered will also be investigated Rab7a is a gene that provides the instructions to make the protein Rab7. Rab7 is one of over sixty Rab proteins identified within mammalian cells, all of which belong to the Ras superfamily. All Rab proteins are involved with the endo/exocytic, secretory pathways and each one associates with its own specific membranes and organelles, although it may share a membrane with another Rab protein. Rab7 has been discovered to function in the late endosomes, lysosomes and the autophagosomes. Like all Rabs, Rab7 is a monomeric GTPase that cycles from an active, GTP-associated, membrane-bound state to a GDP-associated state that is found in the cytosol as part of a complex with the soluble Rab GDP-dissociation inhibitor (GDI). To activate Rab7, a membrane bound guanine nucleotide exchange factor (GEF) is needed. Once the Rab7 has gained a GTP at the loss of GDP and become anchored into a plasma membrane by a hydrophobic lipid anchor, two ‘switch’ regions conformationally change to allow recruitment and binding of other effector proteins that assist with vesicle transport, membrane tethering and fusion. See figure 1. Hydrolysis of GTP is accelerated by GTPase-activating factors (GAPs), and membrane insertion and extraction is partially coupled to nucleotide exchange (Grosshans et al, 2006) ... ...hin the cell may be particularly pronounced in the longer neurites of the extremities, providing support for Spinosa et al’s (2008) previous suggestion that CMT2b mutations affect the longer neurons due to the increased distance that molecules have to travel compared to other neurons. Valproic acid has been found to stimulate neurite growth in the presence of CMT2b-associated Rab7 mutants through Erk. Valproic acid (VPA) is a short-branched fatty acid, a mood stabiliser it is normally used to treat bi-polar disorder, and as an anticonvulsant (Manji et al, 2001 IN: Yamauchi et al, 2010). Yamauchi et al in 2006/2007 reported that VPA promoted neurite growth through the c-jun N-terminal kinase (JNK) pathways in mouse neuroblastoma cells. In 2010, Yamauchi et al studied the effect of VPA in a neuropathy model, again in mouse neuroblastoma cells (N1E-115 cells)

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