Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

Abstract

The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.

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

“…Taken together, these data suggest that disease progression is influenced by a modulation of lipid β-oxidation, involving CS in the translocation of FAs to mitochondria. Since CPT1 plays a key role in mitochondrial processes, many studies have targeted its pharmacological or genetic inhibition [ 52 , 53 , 54 ] to show that the shift from glucose to lipid metabolism is crucial for disease development. Metabolic deregulation has been proposed as a crucial point in the pathogenesis of several neurodegenerative diseases, such as ALS [ 55 ], myotonic dystrophy [ 56 ], Alzheimer’s, and Parkinson’s diseases [ 57 ], where the balance between glucose and lipid oxidation is disturbed, as is the case in HD.…”

“…Metabolic deregulation has been proposed as a crucial point in the pathogenesis of several neurodegenerative diseases, such as ALS [ 55 ], myotonic dystrophy [ 56 ], Alzheimer’s, and Parkinson’s diseases [ 57 ], where the balance between glucose and lipid oxidation is disturbed, as is the case in HD. For HD, enhanced lipid β-oxidation leads to an increase in radical oxygen species and oxidative stress, resulting in defective respiratory chains and ATP deficit [ 39 ], which further drives metabolic deregulation and mitochondrial damage on the one hand, and triggers neurodegeneration on the other [ 49 , 52 ]. Many CPTs and carnitine transporter inhibitors have been tested to target metabolic deregulation in neurological diseases [ 14 , 51 ].…”

Thinking outside the box: non-canonical targets in multiple sclerosis

“…Counterintuitively, mice with a specific mutation in CPT1A , which is associated with low susceptibility to MS in the Inuit population and reduced CPTa1 activity, have reduced disease severity in EAE compared to wild-type mice 204 . Inhibiting FAO via etomoxir reduced CNS inflammation and demyelination in EAE 205 , 206 , indicating that overall reduction of CPT1A activity (and consequently FAO) can ameliorate neuroinflammation.…”

Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies

“…In addition, Taib et al [ 77 ] observed the significant inhibition of cell proliferation when etomoxir was applied alongside oleic acid in GBM and astrocytic cells [ 77 ]. To date, most studies in this area have employed in vitro experiments using gliomas or other cancer cells; however, the literature also contains clinical trials and animal studies demonstrating the inhibitory effects of etomoxir treatment in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease [ 78 ]. Thus, we can assume that BBB crossing is an issue that can be overcome in the case of etomoxir and that more trials examining the use of this drug to treat gliomas are forthcoming.…”