SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD.
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.
Harry Perkins Institute of Medical Research, University of Western Australia, Australia; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Sarah L
SL
Rea
School of Life Sciences, University of Nottingham, UK.
Veronika
V
Majcher
Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham, UK.
Mark S
MS
Searle
School of Life Sciences, University of Nottingham, UK. Electronic address: robert.layfield@nottingham.ac.uk.
Rob
R
Layfield
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001343:Autophagy; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010001:Osteitis Deformans / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
Amyotrophic lateral sclerosis; Autophagy; Frontotemporal lobar degeneration; Paget disease; SQSTM1; p62