Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation

Background: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case. Results: All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state. Conclusions: Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication.

Nitrosopersulfide (SSNO-) targets soluble guanylyl cyclase and induces vasodilation in vivo

Background Recent experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide signaling pathways are intimately intertwined particularly in the vasculature, with mutual attenuation or potentiation of biological responses under control of the soluble guanylyl cyclase (sGC) / phopshodiesterase (PDE) pathway. There is now compelling evidence that part of the NO/sulfide cross talk has a chemical foundation via the formation of S/N-hybrid molecules including thionitrous acid (HSNO) and nitrosopersulfde (SSNO-). The aim of this study was to characterize the bioactive products of the interaction between sulfide and NO metabolites targeting sGC that may potentially regulate vasodilation. Results We found that the chemical interaction of sulfide with NO or nitrosothiols leads to formation of S/N-hybrid metabolites including SSNO- via intermediate formation of HSNO. Contrary to a recent report in the literature but consistent with the transient nature of HSNO, its formation was not detectable by high-resolution mass spectrometry under physiologically relevant conditions. SSNO- is also formed in non-aqueous media by the reaction of nitrite with oxidized sulfur species including colloidal sulfur and polysulfides. SSNO- is stable in the presence of high concentrations of thiols, release NO, and activates sGC in RFL-6 cells in an NO-dependent fashion. Moreover, SSNO- is a potent vasodilator in aortic rings in vitro and lowers blood pressure in rats in vivo. The presence of high concentrations of SOD or thiols does not affect SSNO- mediated sGC activation, while it potentiates and inhibits the effects of the nitroxyl (HNO) donor Angeli's salt, suggesting that HNO release from SSNO- is not involved in sGC activation. Conclusion The reaction between NO and sulfide leads to fomation of S/N-hybrid molecules including SSNO-, releasing NO, activating sGC and inducing vasodilation. SSNO- is considerably more stable than HSNO at pH 7.4 and thus a more likely biological mediator that can account for the chemical cross-talk between NO and sulfide.