The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington’s Disease Model by Acting on the Expression of Carnitine-Related Genes

Abstract

Huntington’s disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes.

The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases

“…An animal study revealed that glycolytic striatal astrocytes had reprogrammed their fuel use and switched to FAO as an alternative energy source in HD [ 85 ]. Moreover, behavioral and transcriptional analyses of the HD Drosophila model demonstrated that the availability of lipids for βOX plays an essential role in developing HD symptoms [ 86 ]. In this study, Teglicar, a reversible inhibitor of CPT1A (also known as ST1326), impaired the oxidation of FAs and the availability of cytosolic acetyl-CoA.…”

“…Therefore, decreased cell reliance on βOX led to a metabolic shift toward glucose oxidation and significantly improved locomotion. It delayed the onset of the disease in the HD Drosophila model [ 86 ].…”

Progress of potential drugs targeted in lipid metabolism research

“…Studies have shown that the combination of ST1326 and ABT199 (Bcl-2 inhibitor) can enhance the anti-acute myeloid leukemia (AML) effect of the latter, indicating that cpt1a may become a potential drug target for the treatment of AML (Ricciardi et al, 2015;Mao et al, 2021). Huntington's disease (HTT) is a severe neurodegenerative disease, and a Drosophila HTT disease model was used to demonstrate that treatment with the cpt1a inhibitor ST1326 can alleviate the symptoms of HTT (Bertapelle et al, 2022). Although the relationship between mitochondrial energy metabolism and HTT disease is still unclear, the development of safe and effective CPT1 inhibitors may be an effective strategy to slow down the development of HTT disease.…”