Effect of nonsense-mediated mRNA decay factor SMG9 deficiency on premature aging in zebrafish

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• SMG9 is crucial for nonsense-mediated mRNA decay (NMD), a cellular quality control pathway.
• Mutations in SMG9 are linked to heart and brain malformation syndrome (HBMS), but the mechanism is unknown.

Purpose of the Study:

• To investigate the in vivo function of SMG9 in adult zebrafish.
• To elucidate the molecular mechanisms underlying SMG9-associated HBMS and premature aging.

Main Methods:

• Generated and analyzed smg9 mutant zebrafish (smg9oi7/oi7) with extended lifespan.
• Assessed congenital abnormalities, cardiac function, and aging phenotypes in mutant zebrafish.
• Quantified NMD target mRNA levels and spermidine oxidase (SMOX) expression.

Main Results:

• smg9 mutant zebrafish exhibited congenital brain abnormalities, reduced cardiac contraction, and a premature aging phenotype.
• A trend toward increased NMD target mRNA levels was observed in mutants.
• Elevated SMOX in mutants led to accumulation of reactive oxygen species and acrolein, causing oxidative stress.

Conclusions:

• SMG9 deficiency dysregulates NMD, leading to SMOX accumulation and oxidative stress.
• This oxidative stress contributes to the premature aging phenotype observed in smg9 mutant zebrafish.
• The findings provide insights into the molecular basis of HBMS and SMG9's role in aging.