[Literature Review] A New Hope for Progeria Treatment: CRISPR Gene Editing Uncovers Protein Synthesis Dysregulation and Novel Therapeutic Targets

On February 16, 2025, Professor Delphine Larrieu and her team from the Cambridge Institute for Medical Research at the University of Cambridge published a groundbreaking study in Nature Communications. Titled “A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein synthesis regulation,” this research employed a genome-wide, multiparametric CRISPR screening approach to uncover the role of BAF in regulating protein synthesis. The findings provide crucial insights into the mechanisms underlying progeria and identify potential therapeutic targets for this condition.

Original Article Link：https://doi.org/10.1038/s41467-025-56916-5

Progeria is a rare genetic disorder characterized by multiple premature aging symptoms, including hair loss, abnormal fat metabolism, cardiovascular dysfunction, and skeletal abnormalities, all of which typically manifest earlier than usual. Néstor-Guillermo Progeria Syndrome (NGPS) is caused by mutations in the BANF1 gene, which encodes the BAF protein—a key player in maintaining nuclear membrane stability and repair. NGPS patients experience severe skeletal dysfunction, such as osteoporosis and skeletal deformities, offering fresh insights for anti-aging research.

This study utilized CRISPR gene editing technology to systematically identify genes that could improve the abnormal phenotypes observed in NGPS cells, shedding light on the potential mechanisms underlying progeria and uncovering new therapeutic targets.

I. Identifying Study Subjects and Phenotypes

Researchers selected fibroblasts derived from NGPS patients and established four cellular phenotypes associated with the BAF A12T mutation: mislocalization of nuclear membrane protein Emerin, increased nuclear deformation, elevated nuclear membrane rupture frequency, and higher micronucleus formation. These phenotypes served as the criteria for their screening.

Figure 1: NGPS fibroblasts exhibit phenotypes distinct from those of HGPS

II. Genome-wide CRISPR Screening

Using CRISPR/Cas9 technology, the researchers conducted a systematic knockout of approximately 20,000 human genes, assessing the impact of their loss on the four identified phenotypes. Employing high-throughput microscopy, they identified 130 candidate genes, and subsequent validation confirmed 43 genes that significantly improved the abnormal phenotypes of NGPS cells.

Figure 2: Identifying genes and pathways that regulate NGPS phenotypes

III. Gene Function Analysis and Validation

Gene Ontology (GO) enrichment analysis revealed that these genes are predominantly involved in biological processes such as protein synthesis, protein and RNA transport, and osteoclast development. Further experimental validation demonstrated that the BAF A12T mutation significantly increases protein synthesis rates in NGPS cells, accompanied by a higher rate of translation errors. This protein synthesis dysregulation may be a key mechanism driving accelerated aging in progeria.

Figure 3: Validated hits that normalize various nuclear membrane phenotypes in NGPS cells

Figure 4: BAF A12T is associated with increased protein synthesis and translation errors

IV. Validation in a C. elegans Model

To confirm the biological relevance of their screening results, researchers conducted experiments using a C. elegans NGPS model carrying the BAF-1 (G12T) mutation. The findings showed that knockdown of several identified genes, including RPS3A and PAFAH1B1, significantly suppressed lethality in the worms, further underscoring the therapeutic potential of these genes in progeria.

Figure 5: Depletion of PAFAH1B1, RPS3A, SMU1, and VPS16 suppressed larval lethality

in the NGPS hermaphrodite C. elegans model

In summary, this study demonstrated the feasibility and effectiveness of CRISPR/Cas9-based genome-wide screening in progeria research; identified several key genes and pathways associated with NGPS, offering new insights into its underlying mechanisms; and suggested that protein synthesis dysregulation may be a shared mechanism driving premature aging. These findings provide a theoretical foundation for developing potential treatments for NGPS.

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