SQSTM1/p62: A Potential Target for Neurodegenerative Disease

Abstract

Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.

Keywords: SQSTM1/p62; autophagy; neurodegenerative diseases.

Figure 1.

Schematic representation of misfolded protein degradation processes, using amyloid fibers as an example. As seen above, misfolded and aggregated protein molecules are eliminated by different mechanisms based on molecule size. In the case of neurodegenerative conditions, mutations or alterations lead to protein misfolding. When these misfolded proteins evade degradation, they are then processed into small-misfolded oligomers, at which point they are toxic to the neuronal environment. Examples of these include α-synuclein, β-amyloid, and poly-Q proteins, oligomers known for their pathological roles in Parkinson’s, Alzheimer’s, and Huntington’s diseases, respectively. Cells have three protective mechanisms by which they can remove misfolded and aggregated proteins from the cellular environment: proteolysis, autophagy, and inclusion body formation. Unfolded peptides and misfolded monomers are eliminated via proteasomal degradation. The majority of misfolded oligomers, in addition to some misfolded monomers, are removed via autophagic clearance. Ubiquitin plays a critical role in all three pathways, as it marks proteins for proteolytic and autophagic degradation and is found in abundance in inclusion bodies.

Figure 2.

Misfolded and aggregated proteins related to neurodegenerative diseases. Abbreviations: AGD, amoebic gill disease, CBD, corticobasal degeneration, NFTPD, neurofibrillary tangle predominant dementia.

Figure 3.

Key components of the autophagy process. Defective regulation and induction of the autophagy process have been associated with many neurodegenerative diseases. Abnormal interactions of mutant superoxide dismutase 1 (mSODl), LRRK2, Parkin, PINK1, and mutant Huntington (mHTT) with Beclin 1 could alter the initiation steps of autophagy. PINK and Parkin play a key role in the elimination of damaged mitochondria and mutations in these proteins, as seen in Parkinson’s disease (PD), and could interfere with overall mitophagy, the selective degradation of mitochondria by autophagy. mHTT expression leads to altered cargo recognition and autophagy failure. α-Synuclein (α-syn) can interfere with autophagy through interaction with Rab1a. Presenilin-1 (PS1) mutations cause impairment in lysosomal acidification and autophagy impairment. In PD, mutations in ATP13A2 could alter the function of lysosomes.

Figure 4.

Trafficking role of p62 in selective macroautophagy.

Figure 5.

Functional domains in p62 with their interacting proteins and related pathways.

Figure 6.

Multiple domains of p62 and its functions related to neurodegenerative diseases.