An ubiquitin-binding protein, p62, is one of the components of the ubiquitin-containing inclusions in several human neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of skein-like inclusions, Lewy body-like inclusions, and basophilic inclusions in the remaining anterior horn cells, in which these inclusions contain ubiquitin, while the other characteristic inclusions of Bunina type are ubiquitin-negative. We examined the spinal cord from 28 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibody to p62. The results demonstrated that p62 localized in skein-like inclusions, Lewy body-like inclusions and basophilic inclusions. The number of p62-positive inclusions observed in the remaining anterior horn cells of each section was variable among the ALS cases. In contrast, Bunina bodies, that do not contain ubiquitin, were negative for p62. As far as we examined, the 11 non-ALS cases did not show any p62 immunoreactivities in the anterior horn cells. Our results suggested that p62 plays important roles in forming the inclusions and may be associated with the protection of the neurons from degenerative processes involving ubiquitin.
"The p62 protein is a stress-responsive ubiquitin-binding protein shown to have a role in degradation of polyubiquitinated proteins via the proteasome pathway or autophagic processes . It is present in neuronal and glial ubiquitin-positive inclusions in different tauopathies and synucleinopathies, including Alzheimer disease, FTLD, dementia with Lewy bodies, Parkinson disease, Huntington disease and multiple system atrophy [15, 20, 23]. Also in FTLD, with or without ALS, p62 co-localizes with TDP-43 and FUS in brain and/or spinal cord [2, 6, 32]. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
"Co-existence of ALS/FTLD and PDB is not widely recognized but has been noted; however it is likely that co-existence is under reported due to the characteristic late-onset of PDB, with the more severe (lethal) symptoms of ALS/FTLD likely precluding PDB diagnosis . The p62 protein has previously been linked to neurodegenerative phenotypes through its localization to ubiquitin-positive cytoplasmic aggregates in many disorders including Alzheimer's and Parkinson's diseases, but also ALS and FTLD   . As of November 2013 eight different studies have reported SQSTM1 mutations in patients with ALS/FTLD (Table 1)        . "
[Show abstract][Hide abstract] ABSTRACT: Paget disease of bone (PDB) is a skeletal disorder common in Western Europe but extremely rare in the Indian subcontinent and Far East. The condition has a strong genetic element with mutations affecting the SQSTM1 gene, encoding the p62 protein, frequently identified. Recently SQSTM1 mutations have also been reported in a small number of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), neurodegenerative disorders in which significant coexistence with PDB has not been previously recognised. Although several SQSTM1 mutations are common to both ALS/FTLD and PDB, many are ALS/FTLD-specific. The p62 protein regulates various cellular processes including NF-κB signaling and autophagy pathways. Here we consider how knowledge of the impact of PDB-associated SQSTM1 mutations (several of which are now known to be relevant for ALS/FTLD) on these pathways, as well as the locations of the mutations within the p62 primary sequence, may provide new insights into ALS/FTLD disease mechanisms.
Experimental Cell Research 01/2014; 325(1). DOI:10.1016/j.yexcr.2014.01.020 · 3.25 Impact Factor
"Alternatively, defects in protein degradation may be involved in the formation of pathological FUS inclusions. Ubiquitin and p62, also known as Sequestosome 1 (SQSTM1), are common components of cytoplasmic protein inclusions in several neurodegenerative disorders, including AD, Parkinson's disease, dementia with Lewy bodies, Huntington's disease (HD) and ALS/FTLD (Kuusisto et al., 2008; Mizuno et al., 2006; Zatloukal et al., 2002). p62/SQSTM1 binds to polyubiquitinated protein aggregates and targets them for degradation in autophagosomes (Pankiv et al., 2007) and its accumulation has been suggested to impair the UPS (Korolchuk et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family.
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