Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons

Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal aging. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased α-synuclein (α-syn) levels. Furthermore, elevated α-syn results in decreased GCase activity. While the role of α-syn in PD remains unclear, evidence indicates that aggregated α-syn fibrils are a pathogenic species in PD, passing between neurons and inducing endogenous native α-syn to aggregate; spreading pathology through the brain. We have investigated if preformed α-syn fibrils (PFFs) impair GCase activity in mouse cortical neurons and differentiated dopaminergic cells, and whether GCase deficiency in these models increased the transfer of α-syn pathology to naïve cells. Neurons treated with PFFs induced endogenous α-syn to become insoluble and phosphorylated at Ser129 to a greater extent than monomeric α-syn-treatment. PFFs, but not monomeric α-syn, inhibited lysosomal GCase activity in these cells and induced the unfolded protein response. Neurons in which GCase was inhibited by conduritol β-epoxide did not increase the amount of insoluble monomeric α-syn or its phosphorylation status. Instead the release of α-syn fibrils from GCase deficient cells was significantly increased. Co-culture studies showed that the transfer of α-syn pathology to naïve cells was greater from GCase deficient cells. This study suggests that GCase deficiency increases the spread of α-syn pathology and likely contributes to the earlier age of onset and increased cognitive decline associated with GBA-PD

Prokaryotic aminopeptidase activity along a continuous salinity gradient in a hypersaline coastal lagoon (the Coorong, South Australia)

The distribution and aminopeptidase activity of prokaryotes were investigated along a natural continuous salinity gradient in a hypersaline coastal lagoon, the Coorong, South Australia. The abundance of prokaryotes significantly increased from brackish to hypersaline waters and different sub-populations, defined by flow cytometry, were observed along the salinity gradient. While four sub-populations were found at each station, three additional ones were observed for 8.3% and 13.4%, suggesting a potential modification in the composition of the prokaryotic communities and/or a variation of their activity level along the salinity gradient. The aminopeptidase activity highly increased along the gradient and salinity appeared as the main factor favouring this enzymatic activity. However, while the aminopeptidase activity was dominated by free enzymes for salinities ranging from 2.6% to 13.4%, cell-attached aminopeptidase activity was predominant in more saline waters (i.e. 15.4%). Changes in substrate structure and availability, strongly related to salinity, might (i) modify patterns of both aminopeptidase activities (free and cell-associated enzymes) and (ii) obligate the prokaryotic communities to modulate rapidly their aminopeptidase activity according to the nutritive conditions available along the gradient

L444P Gba1 mutation increases formation and spread of α-synuclein deposits in mice injected with mouse α-synuclein pre-formed fibrils

Parkinson disease is the most common neurodegenerative movement disorder, estimated to affect one in twenty-five individuals over the age of 80. Mutations in glucocerebrosidase 1 (GBA1) represent the most common genetic risk factor for Parkinson disease. The link between GBA1 mutations and α-synuclein accumulation, a hallmark of Parkinson disease, is not fully understood. Following our recent finding that Gba1 mutations lead to increased α-synuclein accumulation in mice, we have studied the effects of a single injection of mouse α-synuclein pre-formed fibrils into the striatum of Gba1 mice that carry a L444P knock-in mutation. We found significantly greater formation and spread of α-synuclein inclusions in Gba1-transgenic mice compared to wild-type controls. This indicates that the Gba1 L444P mutation accelerates α-synuclein pathology and spread

Neurological disorder in a male llama originated by an abscedative myositis

Background: Early diagnosis of neurological conditions in South American Camelids is crucial for treatments, prognosis and clinical patient development. Infectious agents, parasite, nutritional conditions or trauma, can cause neurological symptoms in camelids. Behavioral particularities can produce late infections and should be considered in differential diagnosis in clinical neurological cases. Case description: A 4-year-old male llama was attended for consultation for a limp in his left hind leg. On clinical examination no general nor hind leg problems were found. After a week of the first consultation he presented an acute disorder to move. A complete neurological exam detected paraplegia with decreased deep sensation and hyporeflexia in the hind limbs were found. Complete blood work analysis and radiographs were performed, a moderate anemia and leucocytosis was detected and, radiographs suggested osteomyelitis on the spinal process in the third lumbar vertebra. Anti-inflammatory and antibiotic treatment with florfenicol was chosen and used at a dose of 20 mg/kg intramuscularly. The male llama died two weeks after the first sign appeared. At postmortem examination the most relevant lesion was a severe inflammatory infiltration delimited with connective tissue in the lumbar muscles, compatible with an abscedative myositis, Enterococcus spp. was isolated in the culture from the lesion. Conclusion: To the authors knowledge this is the first report of a secondary and late infection produced as a consequence of aggressive behavior between males and should be consider as a differential diagnose in neurological disorders in these species.Fil: Fumuso, Fernanda Gabriela. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Instituto de Investigacion y Tecnología en Reproducción Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Carretero, Maria Ignacia. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Instituto de Investigacion y Tecnología en Reproducción Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chaves, M. G.. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Instituto de Investigacion y Tecnología en Reproducción Animal; ArgentinaFil: Arraztoa, Claudia Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Instituto de Investigacion y Tecnología en Reproducción Animal; ArgentinaFil: Veiga, M. F.. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Instituto de Investigacion y Tecnología en Reproducción Animal; ArgentinaFil: Schapira, Andrea. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; ArgentinaFil: Suranitti, A.. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Area de Teriogenología; Argentin

Metabolic Control Analysis in a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease

We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432–46439, 2003). MAO-B mediated increases in H2O2 also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H2O2 generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system

Preterm Infants’ Follow-Up Program at a Public Hospital in Buenos Aires: Two-Decade Study

Objectives: To analyze temporal trends of mortality, morbidity, growth and neurodevelopment until 2 years of corrected age (CA) of very low birth weight infants (VLBWI) born between 1986- 2005 in Ramon Sardá Maternal Infant Hospital (RSMIH). Methods: Descriptive temporal trend study divided in 5 quinquenniums.1255 VLBWI were born at RSMIH between 1986-2005; 46 were excluded (genetic syndromes, major congenital malformations, confirmed intrauterine infections), 84 were referred out and 1125 were studied. Birth weight (BW), gestational age (GA); morbidity; growth; neurodevelopment at 1 and 2 years of CA; neurological and sensorial disorders, antenatal steroids use, breastfeeding; rehospitalizations; mothers´ age and years of schooling and Unsatisfied Basic Needs Index (UBNI) were recorded. Results: Survival rates increased during the last two periods, especially in <1000g BW infants despite the decrease in GA and BW. Children receiving surfactant (Sf), parenteral nutrition (PN) and antenatal steroids (AS) in the last quinquennium obtained better results in growth (40 weeks GA and 1 CA). The use of these therapies increased greatly in the last decade. Also breastfeeding at 40 weeks GA and 4 months tended to be better. Bronchopulmonary dysplasia (BPD) increased. Rehospitalizations (majorly attributable to lower tract infections) and UBNI stayed equal all along. Mothers’ years of schooling increased a little in the last two quinquenniums. Conclusion: In the last quinquennium children tended to be smaller in GA and BW due to an increase in the survival rate as a result of higher technology and appropriate interventions such as AS, PN, Sf, etc

Retinal thinning in Gaucher disease patients and carriers: results of a pilot study

Both Gaucher disease patients and heterozygous glucocerebrosidase mutation carriers are at increased risk of Parkinson's disease. Retinal thinning has been reported in early Parkinson's disease. Here we used optical coherence tomography to demonstrate thinning of the retinal ganglion cell layer in Gaucher disease patients and carriers who manifest clinical markers of potential early neurodegeneration. Optical coherence tomography may help identify Gaucher disease patients and carriers at increased risk of developing Parkinson's disease