P62 Sqstm1 (Sequestosome 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
p62, also known as Sequestosome-1 (SQSTM1), is a multifunctional scaffold protein that serves as the classical selective autophagy receptor in mammalian cells. It plays a central role at the intersection of the ubiquitin-proteasome system, selective autophagy, and multiple cell signaling pathways including NF-κB, mTOR, and Nrf2 oxidative stress response. p62 is encoded by the SQSTM1 gene on chromosome 5q35.[1]
In neurodegenerative diseases, p62 has emerged as a pivotal player due to its dual role: (1) as a cargo receptor that tags and delivers ubiquitinated [protein aggregates] for autophagic degradation, and (2) as a component of the protein inclusions that characterize virtually all major neurodegenerative conditions. p62-positive inclusions are found in the neurofibrillary tangles of Alzheimer's disease, Lewy bodies of Parkinson's disease, and ubiquitinated inclusions of ALS/FTD. Mutations in SQSTM1 are directly linked to familial ALS and frontotemporal dementia, establishing p62 as both a pathological marker and a causal factor in neurodegeneration.[2]
p62 is a 440-amino acid protein with a modular domain architecture that enables its diverse functions:
The spatial arrangement of the LIR and UBA domains allows p62 to simultaneously bind ubiquitinated substrates (via UBA) and autophagosome membranes (via LIR), functioning as a molecular bridge between cargo and the autophagic machinery. Self-oligomerization via the PB1 domain creates large p62 condensates that concentrate cargo, enhancing the efficiency of selective autophagy.[4]
p62 is the prototypical receptor for aggrephagy — the selective autophagic degradation of [protein aggregates]. In neurons, which are post-mitotic and cannot dilute toxic aggregates through cell division, this function is critically important. p62 recognizes and binds:
p62 participates in PINK1/Parkin-dependent mitophagy — the selective degradation of damaged mitochondria. When PINK1 accumulates on depolarized mitochondria and recruits Parkin, the E3 ubiquitin ligase activity of Parkin ubiquitinates outer mitochondrial membrane proteins. p62 recognizes these ubiquitinated mitochondrial substrates and facilitates their engulfment by autophagosomes. Impaired mitophagy due to p62 dysfunction contributes to mitochondrial dysfunction in neurodegeneration.[6]
Through its ZZ and TBS domains, p62 activates the NF-κB inflammatory pathway. In microglia and potentially harmful (via [neuroinflammation) — makes p62 a complex therapeutic target.[7]
When p62 accumulates (e.g., due to autophagy impairment), it sequesters Keap1 via its KIR domain, releasing Nrf2 to translocate to the nucleus and activate antioxidant response element (ARE)-driven genes. This p62-Keap1-Nrf2 axis provides a feedback loop linking autophagy status to the oxidative stress response — a mechanism particularly relevant in neurons under proteotoxic stress.[8]
In Alzheimer's disease, p62 expression is reduced in affected brain regions, particularly the frontal cortex and hippocampus, beginning early in the disease process. This reduction correlates with impaired autophagic clearance of both tau](/proteins/tau-protein) tangles and Amyloid-Beta aggregates. p62 co-localizes with neurofibrillary tangles and is believed to participate in tau](/proteins/tau-protein) degradation via selective autophagy. p62 also modulates APP processing: loss of p62 function shifts APP processing toward the amyloidogenic pathway, increasing Aβ production.[9]
CSF p62 concentrations are significantly elevated in AD patients compared to controls, suggesting that neuronal release of p62 (from dying neurons or exosomal secretion) may serve as a [biomarker] of autophagic dysfunction.[10]
Mutations in SQSTM1 are directly causative of familial ALS and FTD. Over 25 pathogenic variants have been identified, most affecting the UBA domain and impairing ubiquitin binding. Key mutations include:
p62-positive, TDP-43-positive inclusions are the hallmark pathology of sporadic ALS and C9orf72-linked ALS/FTD, indicating that p62-mediated aggregate clearance is overwhelmed in these conditions.[2]
p62 is a consistent component of Lewy bodies, where it co-localizes with ubiquitinated alpha-synuclein. In models of Parkinson's disease, overexpression of p62 enhances alpha-synuclein clearance, while p62 knockdown accelerates aggregate accumulation and neuronal death. The connection between p62 and PINK1/Parkin-mediated mitophagy further links p62 to PD pathogenesis.[5]
p62 recognizes polyglutamine-expanded huntingtin aggregates for autophagic clearance. In Huntington's disease models, enhancing p62 expression or activity promotes aggregate clearance and improves neuronal survival.[5]
Biallelic loss-of-function mutations in SQSTM1 cause a severe childhood-onset neurodegenerative syndrome characterized by progressive cerebellar ataxia, dystonia, and supranuclear gaze palsy, demonstrating that complete loss of p62 function is incompatible with normal neuronal maintenance.[11]
Several strategies are being explored to modulate p62 function therapeutically:
CSF and blood levels of p62 are being investigated as biomarkers for:
The study of P62 Sqstm1 (Sequestosome 1) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.