Sequestosome-1 (p62), also known as SQSTM1, is a multifunctional scaffold protein that plays critical roles in selective autophagy, oxidative stress signaling, and neurodegeneration. It serves as a selective autophagy receptor for protein aggregates and damaged organelles, making it a key player in cellular proteostasis [1].
p62 is encoded by the SQSTM1 gene located on chromosome 5q35.3 and is expressed ubiquitously throughout the body, with high expression in neurons and glial cells of the brain [2]. The protein contains multiple functional domains that enable it to interact with various signaling molecules and participate in diverse cellular processes [3].
p62 possesses several distinct structural domains that confer its multifunctional properties:
p62 serves as a canonical selective autophagy receptor, facilitating the clearance of protein aggregates, damaged mitochondria, and other cellular debris [9]:
p62 plays a central role in the antioxidant response by regulating the Nrf2 (Nuclear factor erythroid 2–related factor 2) pathway [13]:
p62 regulates mTORC1 (mammalian target of rapamycin complex 1) signaling through multiple mechanisms [15]:
In Alzheimer's disease (AD), p62 accumulation is observed in vulnerable brain regions and colocalizes with amyloid plaques and neurofibrillary tangles [17]:
p62 is intimately connected to Parkinson's disease (PD) pathogenesis through its interaction with key PD-related proteins [21]:
p62 inclusions are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [25]:
Targeting p62-mediated autophagy represents a promising therapeutic approach for neurodegenerative diseases [30]:
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