Insights into molecular mechanisms of disease in Neurodegeneration with Brain Iron Accumulation; unifying theories.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterised by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and Ferritin Light Chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis and speculate potential overlap between NBIA subtypes

Gene co-expression networks shed light into diseases of brain iron accumulation

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention

Gene co-expression networks shed light into diseases of brain iron accumulation

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention

The down-regulation of pank2 gene in zebrafish as a model of Pantothenate Kinase Associated Neurodegeneration.

open9siThe increased iron deposition is a hallmark of many neurodegenerative diseases, but its pathogenic role is still unclear. A strong link between iron and neurodegeneration is evident in a set of heterogeneous neurological disorders, known as Neurodegeneration with Brain Iron Accumulation (NBIA). The most common form of inherited NBIA is associated with mutations in hPank2 gene (PKAN). Pank2 is the rate limiting enzyme in CoA biosynthesis and its downregulation in mammalian cells leads to perturbation of cellular iron homeostasis. Here we explore Pank2 biological function in Danio rerio, and propose this system as an important new tool for the study of PKAN disease.openZizioli, Daniela; Tiso, Natascia; Busolin, Giorgia; Khatri, Deepak; Giuliani, Roberta; Borsani, Giuseppe; Monti, Eugenio; Argenton, Francesco; Finazzi, DarioZizioli, Daniela; Tiso, Natascia; Busolin, Giorgia; Khatri, Deepak; Giuliani, Roberta; Borsani, Giuseppe; Monti, Eugenio; Argenton, Francesco; Finazzi, Dari

Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson’s Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons’ Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.National Institutes of Health (NIH

Update on neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) defines a heterogeneous group of progressive neurodegenerative disorders characterized by excessive iron accumulation in the brain, particularly affecting the basal ganglia. In the recent years considerable development in the field of neurodegenerative disorders has been observed. Novel genetic methods such as autozygosity mapping have recently identified several genetic causes of NBIA. Our knowledge about clinical spectrum has broadened and we are now more aware of an overlap between the different NBIA disorders as well as with other diseases. Neuropathologic point of view has also been changed. It has been postulated that pantothenate kinase-associated neurodegeneration (PKAN) is not synucleinopathy. However, exact pathologic mechanism of NBIA remains unknown. The situation implicates a development of new therapies, which still are symptomatic and often unsatisfactory. In the present review, some of the main clinical presentations, investigational findings and therapeutic results of the different NBIA disorders will be presented

BCFT and Sliver state

We give a comment on the possible role of the sliver state in the generic boundary conformal field theory. We argue that for each Cardy state, there exists at least one projector in the string field theory.Comment: Latex, 9 pages, (v2) added a few discussions and reference

Neurodegeneration with Brain Iron Accumulation: Two Additional Cases with Dystonic Opisthotonus

Background: Specific phenomenology and pattern of involvement in movement disorders point toward a probable clinical diagnosis. For example, forehead chorea usually suggests Huntington’s disease; feeding dystonia suggests neuroacanthocytosis and risus sardonicus is commonly seen in Wilson’s disease. Dystonic opisthotonus has been described as a characteristic feature of neurodegeneration with brain iron accumulation (NBIA) related to PANK2 and PLA2G6 mutations. Case report: We describe two additional patients in their 30s with severe extensor truncal dystonia causing opisthotonic posturing in whom evaluation revealed the diagnosis of NBIA confirmed by genetic testing. Discussion: Dystonic opisthotonus may be more common in NBIA than it is reported and its presence especially in a young patient should alert the neurologists to a possibility of probable NBIA

Are high-growth entrepreneurs building the rural economy?

Rural development ; Rural areas