Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation

Park, Goonho; Xu, Ke; Chea, Leon; Kim, Kyle; Safarta, Lance; Song, Keon-Hyoung; Wu, Jian; Park, Soyoung; Min, Hyejung; Hiramatsu, Naoki; Han, Jaeseok; Lin, Jonathan H.

doi:10.1016/j.jbc.2022.102821

Cited by 11 publications

(15 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we extended these investigations to identify additional potential pLoF PERK disease variants. We confirmed previous racial and ethnic disparities in PERK Haplotype B frequency at 4 individual SNPs [12] . Through three-dimensional structural modeling, we reveal how another tauopathy PERK variant, R240H, can induce structural shifts in PERK dimerization and tetramerization.…”

Section: Discussionsupporting

confidence: 89%

“…Structural modeling of tauopathy-linked PERK variants indicated that Haplotype B and the R240H polymorphisms disrupted crucial hydrogen bonds in the luminal domain, potentially altering PERK’s function and stability. Our data supports that many tauopathy-linked PERK variants carry an altered stress-sensing luminal domain but preserved kinase function[12].…”

Section: Introductionsupporting

confidence: 85%

“…Interestingly, most missense mutations associated with Wolcott-Rallison syndrome (WRS) are located within the two cytosolic kinase domains [12,13] and exhibit a high degree of pathogenicity using combinational analysis of 5 bioinformatic tools: PolyPhen-2, PROVEAN, MutationTaster, SIFT, and CADD (Fig. 1D).…”

Section: Genomic Profiling Of Disease-associated Human Perk Mutationsmentioning

confidence: 99%

“…These diseases are associated with distinct genetic variants in the human PERK gene that impact its function. For example, cells expressing the tauopathy-associated Haplotype B PERK variant show reduced kinase activity coupled with increased vulnerability to ER stress-induced damage [11,12] .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Ethnic variation and structure-function analysis of tauopathy-associatedPERKalleles

Park,

Galdamez,

Song

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

SUMMARYEIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss-of-function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of commonPERKpolymorphisms linked to tauopathies. Using SWISS-MODEL, we identified structural perturbations in the ER stress-sensing luminal domain dimers/oligomers of tauopathy-associated PERK variants, Haplotypes A and B, in combination with another tauopathy-linked R240H mutation. Recombinant expression of disease-associated variantsin vitrorevealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non-disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 85%

Section: Genomic Profiling Of Disease-associated Human Perk Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ethnic variation and structure-function analysis of tauopathy-associatedPERKalleles

Park,

Galdamez,

Song

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Loss-of-function mutations in EIF2AK3 , the gene that encodes PERK, are causatively associated with Wolcott-Rallison syndrome – a rare autosomal-recessive disorder that involves multi-organ failures including prominent neonatal or early-childhood insulin-dependent diabetes, kidney and liver dysfunction, and cardiac abnormalities (Delepine et al , 2000; Julier & Nicolino, 2010; Mann et al , 2022). Hypomorphic EIF2AK3 alleles are also implicated in neurodegenerative diseases including the tauopathy progressive supranuclear palsy (PSP) (Hoglinger et al , 2011; Park et al , 2022; Yuan et al , 2018). Further, deficiencies in PERK signaling have been implicated in the pathogenesis of many diseases including PSP and Huntington’s disease (HD) (Almeida et al ., 2022; Bruch et al , 2017; Ganz et al , 2020; Shacham et al , 2021).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Perea

Baron

Dolina

et al. 2023

Preprint

View full text Add to dashboard Cite

The integrated stress response (ISR) is a network of eIF2alpha kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.

show abstract

Ethnic Variation and Structure‐Function Analysis of Tauopathy‐Associated PERK Alleles

Park,

Galdamez,

Song

et al. 2024

Israel Journal of Chemistry

View full text Add to dashboard Cite

EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss‐of‐function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS‐MODEL, we identified structural perturbations in the ER stress‐sensing luminal domain dimers/oligomers of tauopathy‐associated PERK variants, Haplotypes A and B, in combination with another tauopathy‐linked R240H mutation. Recombinant expression of disease‐associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non‐disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.

show abstract

Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation

Cited by 11 publications

References 71 publications

Ethnic variation and structure-function analysis of tauopathy-associatedPERKalleles

Ethnic variation and structure-function analysis of tauopathy-associatedPERKalleles

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Ethnic Variation and Structure‐Function Analysis of Tauopathy‐Associated PERK Alleles

Contact Info

Product

Resources

About