Editorial: Metabolic dysregulation in neurodegenerative diseases

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Abstract
Multiple sclerosis (MS) is a debilitating neurodegenerative disease with a rising prevalence. As an autoimmune disorder that damages myelin-producing cells, most current therapies focus on immunosuppression. However, impaired glucose metabolism is frequently observed in MS patients (Mathur et al.,) Metformin, a widely used diabetes drug, has shown promise in promoting myelin repair in preclinical models and is currently being investigated in clinical trials. It activates AMPK, a key regulator of energy metabolism, yet its effects on oligodendrocytes-the cells responsible for myelin production-and their precursors remain poorly understood.Mohanlall et al., explored metformin's influence on glucose metabolism and oligodendrocyte progenitor differentiation in young mice, as well as its effects in a chemical model of demyelination. Their study found that metformin significantly alters cellular metabolism and enhances the differentiation of precursors into oligodendrocytes, potentially improving myelin repair and function.Neurodegenerative diseases encompass a wide spectrum of disorders, many of which are driven by single pathogenic variants affecting neuronal energy production and mitochondrial metabolism. Studying these genetic mutations provides valuable insights into how glucose metabolism influences neurodegeneration.One of the studies in this topic characterized a novel pathogenic variant of the ACO2 gene, which encodes aconitase 2, a mitochondrial enzyme essential for the TCA cycle and mitochondrial DNA integrity. Mutations in ACO2 have been linked to severe neuropathologies, including infantile cerebellar retinal degeneration. Yang et al., identified new ACO2 variants in an infant patient with cerebellar retinal degeneration. Their analysis revealed compound heterozygous mutations, c.854A>G (p.Asn285Ser) and c.1183C>T (p.Arg395Cys), alongside alterations in metabolic, immune, and neurophysiological pathways. These findings suggest that ACO2 mutations impact more than just mitochondrial function, further highlighting their relevance to neurodegenerative processes.Another work presented in this topic, a thorough review by Santucci et al., examined the role of impaired brain glucose metabolism in Progressive Myoclonus Epilepsies (PMEs)-a group of rare inherited neurological disorders that lead to myoclonus jerks, seizures and progressive neurological decline. Specifically, the review focuses on the subgroup of neuronal ceroid lipofuscinoses (NCLs), where mutations disrupt genes essential for proper lysosomal function The authors discuss glucose hypometabolism as a hallmark of the disease and explore the potential of antidiabetic drugs like metformin and GLP-1 analogs in slowing neurodegeneration. Their review highlights the therapeutic potential of these treatments for PMEs, emphasizing the need for further research.Brain energy metabolism is profoundly influenced by alterations in the blood-brain barrier (BBB), which regulates the transport of nutrients, hormones, and other essential factors. Notably, reduced BBB integrity is frequently observed in Alzheimer's (AD) and Parkinson's disease (PD), contributing to cognitive decline. Lv et al., provide a comprehensive review of the role of platelets in increasing BBB permeability in the context of brain pathology. Their analysis sheds light on how vascular dysfunction contributes to neurodegeneration, emphasizing the importance of further investigation into BBB integrity and its therapeutic implications.The studies compiled in this research topic highlight the intricate relationship between metabolic dysfunction and neurodegeneration. They emphasize the need for an interdisciplinary approach to further explore the underlying mechanisms of this interaction and develop more targeted therapies, including the repurposing of existing metabolic disease treatments.

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