Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Urea cycle disorders (UCD) are inherited metabolic diseases causing high morbidity and mortality due to impaired nitrogen waste clearance.
• Current therapies for UCD are limited, necessitating the development of novel and more effective treatment strategies.
• Beclin-1, a key regulator of autophagy, has emerged as a potential therapeutic target for hyperammonemia.

Purpose of the Study:

• To investigate the therapeutic efficacy of the cell-penetrating, autophagy-inducing Tat-Beclin-1 (TB-1) peptide in mouse models of ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies, the most common UCDs.
• To assess the impact of TB-1 on biochemical parameters and survival rates in proximal and distal UCD models.

Main Methods:

• Utilized spf-ash mice (OTC deficiency model) and AslNeo/Neo mice (ASL deficiency model) to study UCDs.
• Administered the Tat-Beclin-1 (TB-1) peptide to assess its effects on autophagy activation and UCD phenotypes.
• Measured urinary orotic acid, ureagenesis, argininosuccinate levels, survival rates, hepatocellular injury, and glycogen accumulation.

Main Results:

• In OTC-deficient mice, TB-1 treatment reduced urinary orotic acid and improved survival under a protein-rich diet.
• In ASL-deficient mice, TB-1 increased ureagenesis, decreased argininosuccinate levels, and enhanced survival.
• TB-1 treatment also alleviated hepatocellular injury and reduced glycogen accumulation in the ASL deficiency model.

Conclusions:

• Beclin-1-dependent activation of autophagy via the TB-1 peptide demonstrates therapeutic potential for urea cycle disorders.
• This approach effectively improved both biochemical and clinical outcomes in mouse models of proximal (OTC) and distal (ASL) UCDs.
• Autophagy modulation represents a promising therapeutic strategy for inherited defects in nitrogen metabolism.