Blocking β-alanine synthesis triggers widespread perturbations of energy and lipid metabolism in the brain

Background

Glutamate decarboxylase-like 1 (GADL1) decarboxylates aspartic acid to β-alanine in several mammalian tissues, particularly in the brain and skeletal muscle. β-alanine is a precursor to the antioxidant and osmoregulatory dipeptide carnosine (β-alanyl-l-histidine), as well as pantothenic acid and coenzyme A. Deletion of GADL1 reduces carnosine and anserine levels in multiple tissues, but the consequences for brain metabolism remain unclear. This study aimed to explore sex-specific metabolic and cellular effects of GADL1 and β-alanine depletion in different areas of the brain.

Methods and results

We conducted a metabolomic screening of seven mouse tissues, followed by a detailed transcriptomic, proteomic, and metabolomic analysis of cerebrum, cerebellum, and olfactory bulb tissues from male and female GADL1 knockout and wild-type mice to explore sex-, age-, and region-specific molecular alterations. Loss of GADL1 induced distinct, sex-dependent metabolic responses across brain regions. Metabolomic data showed increased oxidative stress and possible synaptic remodeling in the cerebrum of mature females, whereas males exhibited massive lipid accumulation in multiple tissues. A similar pattern appeared in the developing olfactory bulb, where both sexes displayed lipid accumulation, but only males showed signs of inflammatory activation and altered energy metabolism, as supported by transcriptomic and proteomic analyses.

Conclusions

GADL1 loss and consequent β-alanine depletion trigger widespread metabolic remodeling in brain tissue. Even modest β-alanine reduction leads to region, age, and sex-specific perturbations of energy metabolism and cellular homeostasis. These findings highlight the multifaceted biochemical roles of β-alanine and suggest that its physiological and therapeutic effects may differ by tissue, sex, and developmental stage.