ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

Goode, Alice; Rea, Sarah L.; Sultana, Melanie; Shaw, Barry; Searle, Mark S.; Layfield, Robert

doi:10.1016/j.mcn.2016.08.004

Cited by 49 publications

(37 citation statements)

References 38 publications

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“…Our data finds that UBA domain associated p62 disease mutations also have a reduction in UBA domain ubiquitination. More recently, several p62 missense mutations associated with PDB and ALS have been identified within the Keap1 interacting region (Goode et al, 2016b; Wright et al, 2013). These mutations lead to a loss of Keap1 interaction and a reduction in Nrf2 signaling.…”

Section: Discussionmentioning

confidence: 99%

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

et al. 2017

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Summary p62/SQSTM1 (p62) is a scaffolding protein that facilitates the formation and degradation of ubiquitinated aggregates via its self-interaction and ubiquitin binding domains. The regulation of this process is unclear but may relate to the post-translational modification of p62. In the present study, we find that Keap1/Cullin3 ubiquitinates p62 at lysine 420 within its UBA domain. Substitution of lysine 420 with an arginine diminishes p62 sequestration and degradation activity similar to that seen when the UBA domain is deleted. Overexpression of Keap1/Cullin3 in p62-WT expressing cells increases ubiquitinated inclusion formation, p62’s association with LC3 and rescues proteotoxicity. This effect is not seen in cells expressing a mutant p62 that fails to interact with Keap1. Interestingly, p62 disease mutants have diminished or absent UBA domain ubiquitination. These data suggest that the ubiquitination of p62’s UBA domain at lysine 420 may regulate p62’s function and be disrupted in p62 associated disease.

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Section: Discussionmentioning

confidence: 99%

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

et al. 2017

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“…However, other ALS causative mutations, which span throughout the SQSTM1 gene, have been identified, namely E81K, N239K, G297S, E372D, P388S, and P392L, suggesting more complex functions of the protein in disease pathogenesis . Intriguingly, some SQSTM1 mutations are associated with reduced Nrf2 activation in FTLD/ALS , with pharmacological Nrf2 activators showing beneficial effects .…”

Section: Role Of Nrf2 In Autophagymentioning

confidence: 99%

The role of Nrf2 signaling in counteracting neurodegenerative diseases

2018

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The transcription factor Nrf2 (nuclear factor‐erythroid 2 p45‐related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

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“…Some ALS‐associated mutations seem to induce a loss of function in a zebrafish model (Lattante et al , ), and the L341V‐mutant LIR has a greatly reduced ability to bind to LC3‐II (Goode et al , ). Other ALS/FTD‐associated mutations compromise p62's ability to activate the signaling mediated by the transcription factor Nrf2, which is critical for cell defense against oxidative stress, especially in neurons (Goode et al , ). Like p62, optineurin interacts with polyubiquitinated cargo through an LIR domain, an ubiquitin‐binding domain, and a C‐terminal coiled‐coil domain.…”

Section: Autophagymentioning

confidence: 99%

Dysregulated molecular pathways in amyotrophic lateral sclerosis–frontotemporal dementia spectrum disorder

2017

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Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS-FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre-mRNA splicing, stress granule dynamics, and others. These exciting advances reveal the complexity of the pathogenic mechanisms of FTD and ALS and suggest promising molecular targets for future therapeutic interventions in these devastating disorders.

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ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

Cited by 49 publications

References 38 publications

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Dysregulated molecular pathways in amyotrophic lateral sclerosis–frontotemporal dementia spectrum disorder

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