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SQSTM1 mutations – Bridging Paget disease of bone and ALS/FTLD
Authors:Sarah L Rea  Veronika Majcher  Mark S Searle  Rob Layfield
Institution:1. Harry Perkins Institute of Medical Research, University of Western Australia, Australia;2. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia;3. School of Life Sciences, University of Nottingham, UK;4. Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham, UK
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 recognized. 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.
Keywords:ALS  amyotrophic lateral sclerosis  aPKC  atypical protein kinase C  C9orf72  chromosome 9 open reading frame 72  FTD  frontotemporal dementia  FTLD  frontotemporal lobar degeneration  FUS/TLS  fused in sarcoma/translocated in liposarcoma  GWAS  genome-wide association study  IBMPFD  inclusion body myopathy with Paget disease and frontotemporal dementia  IκB  inhibitor of kappaB  IKK  inhibitor of kappaB kinase  Keap1  Kelch-like ECH-associated protein 1  KIR  Keap1-interacting region  LC3  microtubule-associated protein light chain 3  LIR  LC3-interacting region  mTORC1  mammalian target of rapamycin complex 1  NBR1  neighbor of BRCA1 gene 1  NF-κB  nuclear factor kappa B  NGF  nerve growth factor  Nrf2  nuclear factor erythroid 2-related factor 2  OPTN  optineurin  PB1  Phox and Bem1p domain  PDB  Paget disease of bone  PEST  proline  glutamic acid  serine and threonine-rich region  PKCζ/λ  protein kinase Cζ/λ  PTHrP  parathyroid hormone-related protein  RANK  receptor activator of nuclear factor kappa-B  RANKL  receptor activator of nuclear factor kappa-B ligand  SMIR  SOD1 mutant interaction region  SOD1  superoxide dismutase 1  SQSTM1  sequestosome 1  TBS  TRAF6-binding sequence  TDP-43  TAR DNA-binding protein 43  TNFα  tumor necrosis factor alpha  TRAF6  TNF receptor associated factor 6  UBA  ubiquitin-associated domain  UPS  ubiquitin-proteasome system  VCP  valosin containing protein  ZZ  zinc finger domain
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