Pathological protein aggregation Sample Clauses

Pathological protein aggregation. The hallmark pathology of ALS is the presence of cytoplasmic protein aggregates in degenerating motor neurons of FALS and SALS patients (Xxxxxxxx et al., 2013). These protein inclusions are not restricted to motor neurons in the spinal cord but are also present in the frontal and temporal cortices, hippocampus and cerebellum (Xxxxxxxxxx et al., 2011; Xxxxxxxx et al., 2013). The most common aggregates found in ALS patients are ubiquitinated inclusions that can be differentiated in either skein-like inclusions or Lewy body- like hyaline inclusions. Proteins encoded by UBQLN2, FUS, TARDBP, ATXN2, OPTN, VCP and RANT dipeptide repeats derived from the C9ORF72 gene can be found in protein aggregates in affected motor neurons of a large proportion of SALS patients (Xxxxxxxx et al., 2013; Xxxx et al., 2013). Some of these proteins are also present in aggregates of other neurodegenerative diseases such as Alzheimer’s disease, FTD and Huntington’s disease (Xxxxxxxx et al., 2013). The discovery of TDP-43 as the main component of ubiquitinated inclusions in ALS and FTD cases was a major breakthrough (Xxxx et al., 2006; Xxxxxxx et al., 2006). TDP-43 aggregates are found in spinal cord motor neurons, frontal cortex neurons and glial cells in almost all cases of SALS, and in FALS cases caused by mutations in TDP-43 but not in SOD1- or FUS-related cases of ALS (Xxxxxxxxxx et al., 2011; Xxxxxxxx et al., 2013). This cytoplasmic aggregation of C-terminally cleaved, hyperphosphorylated TDP-43 fragments is often accompanied by lowered levels of nuclear TDP-43 (Xxxx et al., 2006; Xxxxxxxx et al., 2013). Although it is unclear how these aggregations modulate toxicity, there are several theories. First, C-terminal fragments of TDP-43 are very aggregation prone, a feature that is enhanced in ALS-linked TDP-43 mutations (Xxxx et al., 2009; Xxxxxx et al., 2009a; Xxxxxxx et al., 2010). Second, the presence of TDP-43 in the cytoplasm is toxic for cells, however, if cytoplasmic TDP-43 is sequestered in inclusion bodies this toxicity may be alleviated (Xxxxxxx et al., 2010). Third, phosphorylation might modulate aggregation and toxicity of TDP-43 (Xxxxx et al., 2010). Inhibition of TDP-43 phosphorylation alleviates the toxic effects of ALS-related TDP-43 mutants in C. elegans (Xxxxxxx et al., 2010; Xxxxxxx et al., 2013). In D. melanogaster, however, hyperphosphorylation reduced overall aggregation formation and toxicity (Li et al., 2011). As mutations in TDP-43 are linked to FALS and SA...
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Pathological protein aggregation. ‌ The accumulation of ubiquitinated proteins in motor neurons is a hallmark pathology of ALS (see for review (Ince et al., 2011)). The major component of the ubiquitinated inclusions was recently identified as TDP-43, a DNA/RNA binding protein (Xxxxxxx et al., 2006). Although TDP-43 resides predominantly in the nucleus in physiological conditions, pathological TDP-43 is cleaved and redistributed to the cytoplasm, where it becomes abnormally phosphorylated and ubiquitinated (Xxxxxxx et al., 2006). Since TARDBP mutations are capable of causing familial and sporadic ALS (Xxxxxxx et al., 2008; Xxxxxxxxxx et al., 2008), it has been speculated that abnormal aggregation of TDP-43 contributes to the disease process. The classical ALS pathology also features accumulations of other proteins. These include phosphorylated neurofilaments, which accumulate in axons and cell bodies and could have detrimental effects on axonal homeostasis (see for review (Xx-Xxxxxxx and Xxxxxx, 2003)) and misfolded SOD1 which is also present in ALS spinal cords (Xxxxxxx et al., 1996) and in SOD1 transgenic animals (Xxxxxx et al., 1998). Antibodies selectively detecting misfolded SOD1 have been created (Xxxxxx et al., 2007) and these label mutant SOD1 inclusions in familial ALS and an oxidized form of wild-type SOD1 in a subset of sporadic ALS cases (Bosco et al., 2010). Finally, mutations in FUS, a nuclear protein, induce its aberrant localization to the cytoplasm, where it forms inclusions (Xxxxxxxxxxx et al., 2009; Xxxxx et al., 2009). Recently, the number of FUS inclusions has been shown to increase with disease duration (Xxxxxx et al., 2012). Other recently identified causative ALS mutations support a role for abnormal protein aggregation in disease pathogenesis. Mutations in the valosin-containing protein (VCP) gene on chromosome 9 have been found in patients with familial ALS (Xxxxxxx et al., 2010). VCP is an abundantly expressed adenosine triphosphate (ATP)ase involved in a wide variety of cellular processes including ER and mitochondrial protein degradation, endosomal sorting, the ubiquitin proteasome system, ER and Golgi reassembly, nuclear envelope formation and the cell cycle (Xxxxxxx et al., 1995; Xxx et al., 2003; Xxx and Xx, 2001; Xxxxxxxxx et al., 1995; Xxxxxxxxx et al., 1995; Xxxx et al., 2011; Xx et al., 2011a). Pathogenic VCP mutations have been found to impair the clearance of aggregated proteins (Ju et al., 2008), perturb endolysosomal sorting (Xxxx et al., 2011) and i...
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