The role of sequestosome 1/p62 protein in amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis

Abstract

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget's disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.

Keywords: aggregate/inclusion body formation; amyotrophic lateral sclerosis-frontotemporal lobar degeneration; autophagy; cell signaling; mitophagy; p62/SQSTM1; protein degradation.

Figure 1

Schematic of p62 domains. p62 self-oligomerizes via its PB1 domain. The LC3-interacting region (LIR) is required for p62 binding to the autophagosome membrane protein LC3, and p62 binds to ubiquitinated substrates via the ubiquitin associated (UBA) domain. p62 regulates Nrf2 signaling through interaction with inhibitory protein Keap1 via the Keap1 interacting region (KIR) domain, and regulates nuclear factor-kappa B (NF-κB) signaling via TRAF6 binding through the TRAF6 binding sequence (TBS) and interaction with RIP via the ZZ domain (Ichimura and Komatsu, 2018).

Figure 2

The effect of p62 on Nrf2 and NF-κB signaling. Upon exposure to oxidative stress, p62 is phosphorylated at Serine residues 403 and 349, and binds to the Nrf2-inhibitory protein Keap1, shuttling it to the autophagosome for degradation. Nrf2 can then enter the nucleus and promote transcription of ARE-genes, including p62, which can also downregulate NF-κB signaling. Keap1: Kelch-like receptor protein 1; NF- κB: nuclear factor-kappa B; Nrf2: nuclear-erythroid factor-2; TRAF6: tumor necrosis factor receptor associated factor 6; ZZ: zinc finger.

Figure 3

The effect of mutant p62 on Nrf2 and NF-κB signaling in ALS and FTLD pathogenesis. Several ALS and FTLD-associated variants exhibit reduced Keap1-binding, preventing Nrf2 from entering the nucleus and promoting protective genes, predisposing the cell death upon exposure to ROS. Upregulation of Nrf2 signaling downregulates NF-κB signaling, indicating that p62 variants that fail to promote Nrf2 signaling may also lead to a concomitant increase in NF-κB signaling. Additionally, several p62 variants are unable to regulate NF-κB signaling, which could potentially lead to increased transcription of pro-inflammatory and pro-apoptotic factors, predisposing the cell to death. ALS: Amyotrophic lateral sclerosis; FTLD: frontotemporal lobar degeneration; FronNrf2: nuclear-erythroid factor-2; NF-κB: nuclear factor kappa-B; ROS: reactive oxygen species.