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.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS.

Aims Most cardiogenic shock (CS) studies focus on acute coronary syndrome (ACS). Contemporary data on temporal trends in patient characteristics, presumed causes, treatments, and outcomes of ACS- and in particular non-ACS-related CS patients are sparse. Methods and results Using nationwide medical registries, we identified patients with first-time CS between 2005 and 2017. Cochrane–Armitage trend tests were used to examine temporal changes in presumed causes of CS, treatments, and outcomes. Among 14 363 CS patients, characteristics remained largely stable over time. As presumed causes of CS, ACS (37.1% in 2005 to 21.4% in 2017), heart failure (16.3% in 2005 to 12.0% in 2017), and arrhythmias (13.0% in 2005 to 10.9% in 2017) decreased significantly over time; cardiac arrest increased significantly (11.3% in 2005 to 24.5% in 2017); and changes in valvular heart disease were insignificant (11.5% in 2005 and 11.6% in 2017). Temporary left ventricular assist device, non-invasive ventilation, and extracorporeal membrane oxygenation use increased significantly over time; intra-aortic balloon pump and mechanical ventilation use decreased significantly. Over time, 30-day and 1-year mortality were relatively stable. Significant decreases in 30-day and 1-year mortality for patients presenting with ACS and arrhythmias and a significant increase in 1-year mortality in patients presenting with heart failure were seen. Conclusion Between 2005 and 2017, we observed significant temporal decreases in ACS, heart failure, and arrhythmias as presumed causes of first-time CS, whereas cardiac arrest significantly increased. Although overall 30-day and 1-year mortality were stable, significant decreases in mortality for ACS and arrhythmias as presumed causes of CS were seen.

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Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.