Journal
MOLECULES
Volume 27, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/molecules27103125
Keywords
Drosophila melanogaster; Huntington's disease; neurodegeneration; L-carnitine; carnitine shuttle; mitochondria; beta-oxidation
Funding
- CNR [0010655/2021]
- RFBR [20-54-7803]
- CNR-Elleva Pharma
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Huntington's disease is a neurodegenerative disorder caused by a gene mutation, and recent studies have found a link between mitochondrial dysfunction and its pathogenesis. Research has shown that pharmacological modification of the carnitine cycle may help improve symptoms.
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.
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