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Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).

ABSTRACT: The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

SUBMITTER: Hinarejos I

PROVIDER: S-EPMC7589120 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).

Hinarejos Isabel I Machuca-Arellano Candela C Sancho Paula P Espinós Carmen C

Antioxidants (Basel, Switzerland) 20201020 10

The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes <i>PANK2</i>, <i>PLA2 ...[more]

PMID: 33092153

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Project description:Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4'-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4'-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.

Project description:Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb-/-) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb-/-) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb-/- mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb-/- mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb-/- mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb-/- mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb-/- mice.

Dataset Information

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).

Publications

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).

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