According to T.F. Gendron et al., partial amounts of the toxicity are due to a gain in function by the protein. When this occurs, the TDP-43 protein has usually shifted its location from the nucleus to throughout the cytoplasm of the cell. This abnormal accumulation of TDP-43 in the cytoplasm is not only found in neurons and glial cells of the primary motor cortex but as well as in brainstem motor nuclei, the spinal cord, and in certain associated white matter tracts (Mackenzie et al 2010). It is at this point that TDP-43 becomes phosphorylated and the C-terminus cleaved resulting in the truncation of the protein (T.F. Gendron et al. 2010; Mackenzie et al 2010). When this occurs, a buildup of the protein C-terminals along with “granules” potentially
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TDP-43 is disposed through a process which involves ubiquitin–proteasome system (UPS). When there is a disturbance in this process it is suggested that it might be the cause increased levels of ubiquitinated TDP-43 within the cell in turn leading neurodegeneration (Lee et al. 2012). Another study described by T.F. Gendron et al. showed that inhibiting autophagic degradation, led to an increase in ubiquitin-positive TDP-43 aggregates with a decrease of nuclear TDP-43 (2010). This suggest that there is more than one mechanism that leads to the ubiquitinizing of …show more content…
2010). It is the phosphorylated proteins that lead to the aggregates within the cytoplasm of the cell. In patients with ALS, once aggregates become mature, they present characteristics of being dense, round, inclusion that are found within the cytoplasm of motor neurons that have been affected by the disease (Lee et al. 2012). It has been suggested that once the protein has become phosphorylated, the half-life of the protein dramatically increases and disrupts the UPS system for degradation and thus leading to an increase in ubiquitinated TDP-43 protein (Lee et al. 2012). According to T.F. Gendron et al., it has been discovered that in yeast, only species that form aggregates and that have intact RRM sequences have been found to be toxic. This has yet to be shown in an animal model but studies are currently in progress. The toxic gain of function of the protein proposed is the aggregation of the proteins due to the phosphorylation of
TDP-43 is disposed through a process which involves ubiquitin–proteasome system (UPS). When there is a disturbance in this process it is suggested that it might be the cause increased levels of ubiquitinated TDP-43 within the cell in turn leading neurodegeneration (Lee et al. 2012). Another study described by T.F. Gendron et al. showed that inhibiting autophagic degradation, led to an increase in ubiquitin-positive TDP-43 aggregates with a decrease of nuclear TDP-43 (2010). This suggest that there is more than one mechanism that leads to the ubiquitinizing of …show more content…
2010). It is the phosphorylated proteins that lead to the aggregates within the cytoplasm of the cell. In patients with ALS, once aggregates become mature, they present characteristics of being dense, round, inclusion that are found within the cytoplasm of motor neurons that have been affected by the disease (Lee et al. 2012). It has been suggested that once the protein has become phosphorylated, the half-life of the protein dramatically increases and disrupts the UPS system for degradation and thus leading to an increase in ubiquitinated TDP-43 protein (Lee et al. 2012). According to T.F. Gendron et al., it has been discovered that in yeast, only species that form aggregates and that have intact RRM sequences have been found to be toxic. This has yet to be shown in an animal model but studies are currently in progress. The toxic gain of function of the protein proposed is the aggregation of the proteins due to the phosphorylation of