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

Comparative distribution of dopamine D-1 and D-2 receptors in the basal ganglia of turtles, pigeons, rats, cats, and monkeys

The distribution and density of dopamine D-1 and D-2 receptors were studied in the basal ganglia of adult turtles, pigeons, rats, cats, and monkeys. Dopamine receptors were measured in vitro by quantitative autoradiography in alternate sections processed for D-1 and D-2 receptor subtypes and compared to adjacent sections stained for acetylcholinesterase (AChE) activity. [ 3 H]-SCH 23390 and [ 3 H]-spiroperidol were used to label the D-1 and D-2 dopamine receptor subtypes, respectively. The anatomic distribution of both D-1 and D-2 receptors in the basal ganglia was remarkably similar across all species examined. Whereas the absolute number of D-1 and D-2 receptors in the basal ganglia varied between species, the percentage of D-1 and D-2 receptors in a region was quite similar among species. The pattern of binding to the D-1 and D-2 receptor varied among the different species. The adult turtles, pigeons, and rats demonstrated non-patchy D-1 and D-2 receptor binding in the striatum and pallidum. The adult cat and monkey caudate nucleus and putamen demonstrated mildly heterogeneous receptor binding in a pattern that differed from that seen with AChE staining, but did occasionally demonstrate similar patterns of the D-1 and D-2 receptor subtypes, The immature cat striatum was characterized by heterogeneous D-1 receptor binding that corresponded to heterogeneous AChE rich patches, whereas D-2 receptor binding was homogeneous. Heterogeneous binding was seen in other basal ganglia structures including the nucleus accumbens, olfactory tubercle, and substantia nigra pars compacta and reticulata. Complementary D-1 and D-2 receptor binding patterns were seen in the pallidum and substantia nigra of the mammals. The results of this study indicate that both D-1 and D-2 dopamine receptors are present in the basal ganglia of five different vertebrates. A common feature of dopamine receptors in the basal ganglia is their heterogeneity in distribution and density. The heterogeneity of dopamine receptors has similarities to and differences from the distribution of presynaptic dopamine and other neurotransmitter markers of the basal ganglia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50037/1/902620308_ftp.pd

Inter-subunit interactions that coordinate Rad51's activities

Rad51 is the central catalyst of homologous recombination in eukaryotes and is thus critical for maintaining genomic integrity. Recent crystal structures of filaments formed by Rad51 and the closely related archeal RadA and eubacterial RecA proteins place the ATPase site at the protomeric interface. To test the relevance of this feature, we mutated conserved residues at this interface and examined their effects on key activities of Rad51: ssDNA-stimulated ATP hydrolysis, DNA binding, polymerization on DNA substrates and catalysis of strand-exchange reactions. Our results show that the interface seen in the crystal structures is very important for nucleoprotein filament formation. H352 and R357 of yeast Rad51 are essential for assembling the catalytically competent form of the enzyme on DNA substrates and coordinating its activities. However, contrary to some previous suggestions, neither of these residues is critical for ATP hydrolysis

Separation of Recombination and SOS Response in Escherichia coli RecA Suggests LexA Interaction Sites

RecA plays a key role in homologous recombination, the induction of the DNA damage response through LexA cleavage and the activity of error-prone polymerase in Escherichia coli. RecA interacts with multiple partners to achieve this pleiotropic role, but the structural location and sequence determinants involved in these multiple interactions remain mostly unknown. Here, in a first application to prokaryotes, Evolutionary Trace (ET) analysis identifies clusters of evolutionarily important surface amino acids involved in RecA functions. Some of these clusters match the known ATP binding, DNA binding, and RecA-RecA homo-dimerization sites, but others are novel. Mutation analysis at these sites disrupted either recombination or LexA cleavage. This highlights distinct functional sites specific for recombination and DNA damage response induction. Finally, our analysis reveals a composite site for LexA binding and cleavage, which is formed only on the active RecA filament. These new sites can provide new drug targets to modulate one or more RecA functions, with the potential to address the problem of evolution of antibiotic resistance at its root