SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer’s Disease?

Krishnan, Dhanya; Menon, R. G.; Gopala, Srinivas

doi:10.1007/s10571-020-01023-w

Cited by 7 publications

(3 citation statements)

References 149 publications

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“…This discovery also reveals the relationship between AD and the environment. Additionally, SHANK-associated RH domain-interacting protein (SHARPIN) is a multifunctional protein with the role of an inflammatory activator, which could regulate the peripheral macrophages, thereby adjusting Aβ degradation and inflammatory mechanisms [ 39 ]. The clearance of Aβ depends on many factors.…”

Section: β-Amyloid-related Pathway and Pathogenesismentioning

confidence: 99%

Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Wu¹,

Ding²,

Cheng³

et al. 2022

Aging and disease

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The amyloid cascade hypothesis has always been a research focus in the therapeutic field of Alzheimer’s disease (AD) since it was put forward. Numerous researchers attempted to find drugs for AD treatment based on this hypothesis. To promote the research of anti-AD drugs development, the current hypothesis and pathogenesis were reviewed with expounding of β-amyloid generation from its precursor protein and related transformations. Meanwhile, the present drug development strategies aimed at each stage in this hypothesis were also summarized. Several strategies especially immunotherapy showed the optimistic results in clinical trials, but only a small percentage of them eventually succeeded. In this review, we also tried to point out some common problems of drug development in preclinical and clinical studies which might be settled through multidisciplinary cooperation as well as the understanding that reinforces the amyloid cascade hypothesis.

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Section: β-Amyloid-related Pathway and Pathogenesismentioning

confidence: 99%

Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Wu¹,

Ding²,

Cheng³

et al. 2022

Aging and disease

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“…SHANK-associated RH domain interactor (SHARPIN) is a highly conserved protein expressed in various types of cells and tissues. 1 SHARPIN protein consists of three domains: the amino-terminal coiled-coil domain, ubiquitin-like domain, and NPL4 zinc finger domain. 2 These three domains facilitate the interaction between SHARPIN and its target protein and ubiquitin-mediated degradation.…”

Section: Introductionmentioning

confidence: 99%

Characterization of SHARPIN knockout Syrian hamsters developed using CRISPR/Cas9 system

Miao

Lan

Guo

et al. 2022

Anim Models and Exp Med

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BackgroundSHARPIN (SHANK‐associated RH domain interactor) is a component of the linear ubiquitination complex that regulates the NF‐κB signaling pathway. To better understand the function of SHARPIN, we sought to establish a novel genetically engineered Syrian hamster with SHARPIN disruption using the CRISPR/Cas9 system.MethodsA single‐guide ribonucleic acid targeting exon 1 of SHARPIN gene was designed and constructed. The zygotes generated by cytoplasmic injection of the Cas9/gRNA ribonucleoprotein were transferred into pseudopregnant hamsters. Neonatal mutants were identified by genotyping. SHARPIN protein expression was detected using Western blotting assay. Splenic, mesenteric lymph nodes (MLNs), and thymic weights were measured, and organ coefficients were calculated. Histopathological examination of the spleen, liver, lung, small intestine, and esophagus was performed independently by a pathologist. The expression of lymphocytic markers and cytokines was evaluated using reverse transcriptase‐quantitative polymerase chain reaction.ResultsAll the offspring harbored germline‐transmitted SHARPIN mutations. Compared with wild‐type hamsters, SHARPIN protein was undetectable in SHARPIN−/− hamsters. Spleen enlargement and splenic coefficient elevation were spotted in SHARPIN−/− hamsters, with the descent of MLNs and thymuses. Further, eosinophil infiltration and structural alteration in spleens, livers, lungs, small intestines, and esophagi were obvious after the deletion of SHARPIN. Notably, the expression of CD94 and CD22 was downregulated in the spleens of knockout (KO) animals. Nonetheless, the expression of CCR3, CCL11, Il4, and Il13 was upregulated in the esophagi. The expression of NF‐κB and phosphorylation of NF‐κB and IκB protein significantly diminished in SHARPIN−/− animals.ConclusionsA novel SHARPIN KO hamster was successfully established using the CRISPR/Cas9 system. Abnormal development of secondary lymphoid organs and eosinophil infiltration in multiple organs reveal its potential in delineating SHARPIN function and chronic inflammation.

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“…APP, presenilins (PSENs), and Tau variants have shown small contributions to the total heritability of late-onset AD 10,12 , whereas the APOE locus explains approximately a quarter of the disease heritability 13 . The GWAS loci have been suggested to highlight several pathways in AD pathogenesis, spanning microglial activation, lipid metabolism, focal adhesion, and Aβ turnover [14][15][16][17] . Nevertheless, the causal significance of Aβ in AD is a matter of ongoing debate [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

An Amyloid Agnostic Reformulation of the Alzheimer’s Disease: The Long Gene Vulnerability Hypothesis

Soheili-Nezhad¹

2021

Preprint

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Alzheimer’s disease (AD) is a genetically complex senile neurodegeneration with unknown etiology. The first gene discovered to be mutated in early-onset AD, the amyloid precursor protein (APP), has been widely assumed as a causal factor in the disease cascade due to its generation of Aβ species. APP has an evolutionarily conserved biological role and activates a signaling program with notable similarities to integrin—a cell adhesion receptor with a wide array of functions. Intriguingly, several AD genome-wide association study (GWAS) candidate genes, including the SHARPIN locus recently reported by us and others, influence signaling of the integrin pathway. Integrins are focal adhesion regulators and serve in nervous system development, synaptic plasticity, and Tau phosphorylation. These observations suggest that the function of APP probably goes beyond Aβ generation in AD. Aging—the strongest risk factor for AD—is associated with various clock-like events in cells. For instance, neurons are continuously impacted by stochastic ‘hits’ to their genomes in aging, in the forms of DNA damage, insertion-deletions, copy-number variations (CNVs) and other types of somatic mutations. DNA damage and somatic mutations can result in neoplastic changes and cancer in mitotically active cells. However, their consequences in post-mitotic cells such as aging neurons are less defined. The current hypothesis holds that the stochastic loss of DNA sequence data at random loci in aging affects longer genes by chance more frequently. As a result, the biological processes coordinated by long genes may be more vulnerable to such random aging effects. Curiously, as shown by us and others, long genes are strongly enriched for synapse- and cell adhesion-related ontologies, more than any other biological process or cellular compartment. In addition, among various cell types, neurons possess the highest levels of long gene expression and are therefore more vulnerable to such harmful effects. The long gene vulnerability hypothesis provides a simple link between aging and the genetic landscape of AD and warrants new strategies for disease modification.

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SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer’s Disease?

Cited by 7 publications

References 149 publications

Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

Characterization of SHARPIN knockout Syrian hamsters developed using CRISPR/Cas9 system

An Amyloid Agnostic Reformulation of the Alzheimer’s Disease: The Long Gene Vulnerability Hypothesis

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