Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation

Wang, Zhi-Bin; Liu, Junyan; Xu, Xiaojing; Mao, Xiao‐Yuan; Zhang, Wei; Zhou, Hong‐Hao; Liu, Zhao‐Qian

doi:10.1016/j.biopha.2019.109068

Cited by 33 publications

(37 citation statements)

References 84 publications

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“…Between them, C19ORF12 would act as a regulatory protein for human MgtE transporters and the alteration of magnesium has been related to the progression of many neurodegenerative disorders [ 134 , 138 ]. More recently, a correlation among ferroptosis and MPAN has been established by the fact that both pathological situations share lipid peroxidation and mitochondria perturbation as major pathways of cell death [ 139 ].…”

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

“…The reduction of the enzymatic activity or its complete depletion, caused by the different mutations located throughout the protein, could explain the variability in the severity of the phenotypes. Further investigation to elucidate the underlying disease mechanism is required to develop an adequate therapy, as nowadays treatments are restricted to ameliorating the symptomatology [ 139 ].…”

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

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

et al. 2020

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“…NBIAs are a group of at least 12 very rare, clinically and genetically inherited neurodegenerative disorders characterized by deposition of iron generally (but not in all NBIAs) within the basal ganglia, and most specifically, in the globus pallidus and SN (see Table 1). [400][401][402][403] These are regions of the brain that normally have a high iron content and are therefore selectively vulnerable to any further elevation of iron. Neuropathologically, NBIAs are often associated with cerebral, cerebellar and optic atrophy, and retinal degeneration.…”

Section: Neurodegeneration With Brain Accumulation Disordersmentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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“…Infantile neuroaxonal dystrophy (INAD, NBIA2A; MIM# 256600) is a major subtype of PLA2G6-associated neurodegeneration (PLAN), a heterogenous group of clinical disorders with varying severity comprising INAD, atypical neuroaxonal dystrophy (NBIA2B; MIM# 610217) and adult-onset dystonia-parkinsonism (PARK14; MIM# 612953). PLAN is caused by biallelic pathogenic variants in PLA2G6, and the speci c phenotype of PLAN is based on various clinical, genotype-phenotype, neurophysiologic, radiographic, and laboratory features (1,2).…”

Section: Introductionmentioning

confidence: 99%

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

Atwal

Midei

Adams

et al. 2020

Preprint

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Background: INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INADMethods: We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. Results: We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 x 10-07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset.Conclusion: We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

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Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation

Cited by 33 publications

References 84 publications

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

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

Overdosing on iron: Elevated iron and degenerative brain disorders

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

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