Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

Enhancement of antimicrobial activities of whole and sub-fractionated white tea by addition of copper (II) sulphate and vitamin C against 'Staphylococcus aureus'; a mechanistic approach.

WT showed no efficacy in the combinations tested. WTF was enhanced with copper (II) sulphate and further with vitamin C. WT and WTF increased acidity of copper (II) sulphate possibly via the formation of chemical complexes. The difference in WT/WTF absorbance possibly represented substances less concentrated or absent in WTF. Investigations to establish which WTF component/s and in what proportions additives are most effective against target organisms are warranted

Cyclized NDGA modifies dynamic α-synuclein monomers preventing aggregation and toxicity.

Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders

FRI0219 MEPOLIZUMAB FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS IN REAL WORLD DATA

Objectives:To investigate the treatments of eosinophilic granulomatosis with polyangiitis (EGPA) and evaluate the usage of mepolizumab in clinical settings.Methods:The subjects were consecutive EGPA patients who were hospitalized and treated at our department and the Rheumatology, Department of Internal Medicine IV, Osaka Medical College between 2002 and 2018. Their clinical data, treatments, and courses were examined, and the usage of mepolizumab was evaluated.Results:Of 49 EGPA patients, 41 could be analyzed (14 males and 27 females, mean age of onset: 56.4 years). The percentage of positive ANCA was 31.7%, and affected sites were peripheral nerve (92%), central nervous system (17%), skin (51%), ENT (39%), lungs (29%), heart (22%), digestive organs (12%), and kidneys (15%). Remission induction therapy was performed with PSL (41 cases, 100%), PSL pulse (16 cases, 39%), IVCY (17 cases, 41%), RTX (4 cases, 10%), IVIG (22 cases, 54%), AZA (22 cases, 54%), MTX (4 cases, 10%), MMF (2 cases, 5%), MIZ (1 case, 2%), and MEPO (1 case, 2%). Maintenance therapy was performed with PSL (41 cases, 100%), AZA (21 cases, 51%), MTX (6 cases, 15%), MMF (2 cases, 5%), MIZ (3 cases, 7%), and MEPO (10 cases, 24%). In 10 patients who received mepolizumab, the percentage of positive ANCA was 40%, and the median dose of PSL was reduced from 9.5 mg to 5.5 mg after administration. Neither relapses nor adverse events occurred in patients who had received mepolizumab.Conclusion:Mepolizumab reduced the dose of steroids and improved tolerability in EGPA patients with or without ANCA.Disclosure of Interests:None declared</jats:sec