SHARPIN – Alzheimer disease

The association between SHARPIN (HGNC:25321) and Alzheimer disease (MONDO_0004975) is supported by multiple lines of evidence gathered from large-scale genetic association studies and detailed functional assessments. Recent investigations have identified missense variants in SHARPIN that significantly correlate with altered brain imaging phenotypes, including changes in hippocampal volume and entorhinal cortical thickness, suggesting its potential role in disease pathogenesis (PMID:34785643).

Genetic evidence stems from extensive case‑control studies reported in independent cohorts. In one pivotal study conducted in a Korean cohort of over 2600 individuals, a missense variant in SHARPIN was robustly associated with Alzheimer disease-specific brain damages among affected individuals (PMID:34785643). Moreover, an independent Japanese study examining 4563 cases further identified a rare variant that appears to increase the risk of late‑onset Alzheimer disease, thereby reinforcing the genetic association (PMID:31216982).

The variant spectrum in SHARPIN relevant to Alzheimer disease includes missense changes that impact protein function. Notably, the variant formatted as c.556G>A (p.Gly186Arg) has been reported in the literature and serves as an illustrative example of how a single amino acid substitution may disrupt normal protein interactions and downstream signaling pathways. This variant, along with other risk alleles, underscores the contribution of SHARPIN to disease risk and broadens our understanding of its molecular pathology (PMID:31216982).

Functional studies further support the role of SHARPIN in Alzheimer disease pathogenesis. Experiments demonstrate that altered SHARPIN protein function leads to attenuation of NF-κB activation, a key mediator of inflammatory responses in the brain. In vitro assays and molecular dynamics simulations have highlighted that these detrimental functional changes converge on impaired signaling pathways, which are consistent with the neurodegenerative processes observed in Alzheimer disease (PMID:34785643).

Integrating the genetic and functional evidence, the association between SHARPIN and Alzheimer disease appears robust. The convergence of findings from imaging genetics, rare variant analyses, and mechanistic studies provides a coherent narrative in which SHARPIN contributes to disease risk through its role in modulating inflammatory and immune responses. Although Alzheimer disease is complex and multifactorial, the evidence for SHARPIN exceeds what is required for a strong gene‑disease association.

Key take‑home: The combined genetic and functional evidence implicates SHARPIN as a strong risk factor in Alzheimer disease, providing valuable insights for diagnostic decision‑making, risk stratification, and potential therapeutic development.

References

• Translational psychiatry • 2021 • A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages PMID:34785643
• Molecular medicine (Cambridge, Mass.) • 2019 • A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease PMID:31216982
• Nature communications • 2021 • Common variants in Alzheimer's disease and risk stratification by polygenic risk scores PMID:34099642

Evidence Based Scoring (AI generated)