CPT1 Enzyme May Be Potential Therapeutic Target for Parkinson’s
Suppressing CPT1 activity led to reductions in symptoms in 2 mouse models
Suppressing the activity of carnitine palmitoyl-transferase 1 (CPT1) — a key enzyme in the metabolism of fatty molecules — led to reductions in motor and non-motor symptoms in two mouse models of Parkinson’s disease, a new study shows.
These benefits were associated with a normalization of blood sugar, or glucose, metabolism, and reductions in biomarkers of Parkinson’s, as well as in oxidative stress, mitochondrial dysfunction, and neuroinflammation — all implicated in the disease.
Oxidative stress is a type of cellular damage that is partly driven by the resulting products of mitochondria, the cell’s powerhouses.
Additionally, CPT1 suppression improved the bacterial composition of the animals’ gut toward a more neuroprotective profile.
The study, “Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease,” was published in the journal npj Parkinson’s Disease.
Glucose metabolism linked to Parkinson’s progression
Parkinson’s disease is characterized by the progressive death and dysfunction of nerve cells in a brain region, called the substantia nigra, that has a key role in movement control. This leads to the onset of motor symptoms that are the hallmark of Parkinson’s, alongside varied non-motor symptoms and disrupted cellular mechanisms.
One such disruption occurs in the metabolism of glucose, with previous studies showing that glucose metabolism is affected in Parkinson’s and linked to disease progression. This dysfunction may explain similar observations in relation to changes in the metabolism of a type of fatty molecule called fatty acids.
A crucial step in fatty acid metabolism is a process called beta-oxidation, which generates energy from these molecules and is dependent on an enzyme called CPT1. This enzyme, which is located in mitochondria, appears in the body in three forms: CPT1A, found in most cells, CPT1B, mainly found in muscle cells, and CPT1C, found in the brain.
A research team in Denmark previously studied CPT1 in the context of multiple sclerosis and depression using mouse models. They found that blocking CPT1 function had beneficial effects in several disease mechanisms, including lowering inflammation levels and restoring glucose metabolism.
Armed with this knowledge, the team set out to investigate the effects of suppressing CPT1 function in two Parkinson’s mouse models.
They first used a model generated through exposure to the pesticide rotenone, which induces some motor and biochemical changes that are similar to those caused by Parkinson’s in humans.
Before rotenone administration, some of these mice were genetically modified to carry a mutation in the Cpt1a gene, which causes CPT1A activity to be reduced to 22% of normal levels.
[CPT1 suppression] is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of [Parkinson’s disease in the brain].
CPT1A deficiency prevented onset of impairments
Results showed that CPT1A deficiency prevented the onset of motor, muscle strength, and cognitive impairments associated with rotenone exposure, with the animals showing similar performances to healthy mice.
“This demonstrated that the toxic chronic rotenone mouse model was induced successfully, and that [Cpt1a mutation] conferred some resistance” against motor and non-motor symptoms, the researchers wrote.
The rotenone-induced mouse model also showed increased levels of glucose and LDL cholesterol, also known colloquially as “bad cholesterol,” which were not observed in those lacking CPT1A.
Similar results were observed for brain levels of common Parkinson’s biomarkers, such as alpha-synuclein and dopamine, as well as markers of inflammation and oxidative stress, with the Cpt1a mutation conferring protection against the effects of rotenone.
Of note, the alpha-synuclein protein forms toxic clumps in Parkinson’s, and dopamine is the major brain chemical messenger that is progressively lost in the disease.
To check if comparable results could be achieved through a general CPT1 suppression, these experiments were repeated, but now through administration of etomoxir, a small molecule that blocks the activity of all CPT1 forms, following rotenone exposure.
The team found that etomoxir treatment, like the Cpt1a mutation, was effective in reducing Parkinson-like features induced by rotenone.
The effects of etomoxir-based CPT1 suppression were then assessed in a second mouse model that carried mutations in the Park2 gene. In humans, such mutations have been linked to early-onset Parkinson’s and to changes in fatty acid metabolism.
Etomoxir treatment was found to ease muscle weakness, cognitive impairments, and anxiety-like behavior in the mouse model, while restoring glucose levels and reducing the brain levels of pro-inflammatory and oxidative stress markers.
However, some markers, such as cholesterol imbalance, were not significantly changed with etomoxir.
Researchers tested effects of CPT1 suppression in gut microbiome
Finally, the team evaluated the effects of CPT1 suppression in the gut microbiome, the large and diverse group of microorganisms that populate the gut. The gut microbiome modulates, and is modulated by, metabolism, and it has been shown to be altered in Parkinson’s patients.
They found that rotenone exposure led to gut microbiome changes in both healthy mice and Park2 mutated mice that might result in decreased glucose metabolism and increased inflammation. However, these changes were attenuated by etomoxir treatment.
Similarly, Cpt1a mutant mice exposed to rotenone maintained a gut microbiome with more bacterial species linked to protective mechanisms and fewer species associated with disease mechanisms.
The observed “changes in gut microbiome could potentially affect mechanisms such as gut permeability, inflammation, deposition of [alpha-synuclein] and thereby disease [features],” the researchers wrote.
These findings show that CPT1 suppression “is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of [Parkinson’s disease]” in the brain, the team wrote, adding that more detailed studies are needed to understand the mechanisms involved within and outside the brain.
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