HSPA8 knock-down induces the accumulation of neurodegenerative disorder-associated proteins.

Heat shock protein 70 family was demonstrated to play a critical role in protein homeostasis, a process profoundly impaired in neurodegenerative disorders. Neurodegenerative diseases are characterized by the accumulation of different kind of proteins and the formation of insoluble aggregates which are toxic for neurons. To explore the role of heat shock protein family 70 (in particular HSPA8 and HSPA1A) in the accumulation of proteins implied in neurodegeneration pathogenesis, in this study we verified in human SH-SY5Y neuroblastoma cells how HSPA8 or HSPA1A knock-down can affect protein levels of tau, superoxide dismutase 1 and α-synuclein.

HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation.

: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. : Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls.

NMR-driven identification of anti-amyloidogenic compounds in green and roasted coffee extracts.

To identify food and beverages that provide the regular intake of natural compounds capable of interfering with toxic amyloidogenic aggregates, we developed an experimental protocol that combines NMR spectroscopy and atomic force microscopy, in vitro biochemical and cell assays to detect anti-Aβ molecules in natural edible matrices. We applied this approach to investigate the potential anti-amyloidogenic properties of coffee and its molecular constituents. Our data showed that green and roasted coffee extracts and their main components, 5-O-caffeoylquinic acid and melanoidins, can hinder Aβ on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line.

Rotenone down-regulates HSPA8/hsc70 chaperone protein in vitro: A new possible toxic mechanism contributing to Parkinson's disease.

HSPA8/hsc70 (70-kDa heat shock cognate) chaperone protein exerts multiple protective roles. Beside its ability to confer to the cells a generic resistance against several metabolic stresses, it is also involved in at least two critical processes whose activity is essential in preventing Parkinson's disease (PD) pathology. Actually, hsc70 protein acts as the main carrier of chaperone-mediated autophagy (CMA), a selective catabolic pathway for alpha-synuclein, the main pathogenic protein that accumulates in degenerating dopaminergic neurons in PD.

Reduced expression of the chaperone-mediated autophagy carrier hsc70 protein in lymphomonocytes of patients with Parkinson's disease.

Chaperone-mediated autophagy (CMA) impairment is recognized to play a pathogenetic role in Parkinson's disease (PD). A reduced expression of lysosomal-associated membrane protein (lamp) 2A and heat shock cognate (hsc) 70 protein, the two key regulators of CMA, has been reported in brains of PD patients. To verify the existence of a possible systemic CMA dysfunction in PD, in this study the expression of hsc70 and lamp2A was assessed in peripheral blood mononuclear cells (PBMC) of patients with sporadic PD and compared to healthy subjects.

Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation inhibition.

Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson's disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation.

Analysis of vesicular monoamine transporter 2 polymorphisms in Parkinson's disease.

Generation of reactive oxygen species during dopamine (DA) oxidation could be one of the factors leading to the selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake dopamine into synaptic vesicles, preventing its cytoplasmic accumulation and toxic damage to nigral neurons. Polymorphisms in VMAT2 gene and in its regulatory regions might therefore serve as genetic risk factors for PD.

Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.

Background: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission.

Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients.

Valproate (VPA) is an anti-epileptic and mood-stabilizing drug with a broad range of action and which mechanism of action still remains in part elusive. Recently the discovery that VPA modifies the epigenome increasing the transcriptional rate of target genes raises the issue of understanding the exact role of this mechanism. In this work we tested the possibility that VPA could modify the epigenome of lymphomonocytes (PBMC) obtained from epileptic patients chronically treated in monotherapy with VPA and phenobarbital.

Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium.

Association analysis of PARP1 polymorphisms with Parkinson's disease.

Alpha-synuclein accumulation in intracellular inclusions, oxidative stress and microglia-mediated inflammation in the substantia nigra are crucial events in the pathogenesis of Parkinson's disease (PD). Poly (ADP-ribose) polymerase-1 (PARP1), a DNA-binding enzyme and transcriptional regulator, plays an important role in modulating the cellular response to oxidative stress, inflammatory stimuli, and in apoptotic cell death. Inhibition of PARP1 results in significant neuroprotection in PD animal models; moreover PARP1 has a physiological role in the regulation of alpha-synuclein expression.

Nonfibrillar Abeta 1-42 inhibits glutamate uptake and phosphorylates p38 in human fibroblasts.

Alzheimer disease (AD) is the most prevalent neurodegenerative disease, characterized by an increased deposition of β-amyloid (Abeta) within the central nervous system, leading to neuronal death. The availability of effective models, in which confirming novel pathogenic hypotheses and developing therapeutic targets, represents a very important goal for the field of AD. Fibroblasts from these patients may be relevant models in which addressing these issues, as they display biochemical alterations mirroring SNC ones.

Vesicular monoamine transporter 2 mRNA levels are reduced in platelets from patients with Parkinson's disease.

Despite advances in neuroimaging, the diagnosis of idiopathic Parkinson's disease (PD) remains clinical. The identification of biological markers for an early diagnosis is of great interest to start a neuroprotective therapy aimed at slowing, blocking or reversing the disease progression. Vesicular monoamine transporter 2 (VMAT2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and release.

Transmitted HIV Type 1 drug resistance and Non-B subtypes prevalence among seroconverters and newly diagnosed patients from 1992 to 2005 in Italy.

The patterns of transmitted drug-resistant (TDR) HIV-1 variants, non-B subtype spread, and epidemiological trends were evaluated either in seroconverters or in newly diagnosed individuals in Italy over a 13-year period. We analyzed 119 seroconverters, enrolled from 1992 to 2003 for the CASCADE study, and 271 newly diagnosed individuals of the SPREAD study (2002-2005), of whom 42 had a known seroconversion date. Overall, TDR was 15.

Transmission of drug-resistant HIV-1 is stabilizing in Europe.

The SPREAD Programme investigated prospectively the time trend from September 2002 through December 2005 of transmitted drug resistance (TDR) among 2793 patients in 20 European countries and in Israel with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection. The overall prevalence of TDR was 8.4% (225 of 2687 patients; 95% confidence interval [CI], 7.

Recombination analysis and structure prediction show correlation between breakpoint clusters and RNA hairpins in the pol gene of human immunodeficiency virus type 1 unique recombinant forms.

Recombination is recognized as a primary force in human immunodeficiency virus type 1 (HIV-1) evolution, increasing viral diversity through reshuffling of genomic portions. The strand-switching activity of reverse transcriptase is required to complete HIV-1 replication and can occur randomly throughout the genome, leading to viral recombination. Some recombination hotspots have been identified and found to correlate with RNA structure or sequence features.

Identification of a possible ancestor of the subtype A1 HIV Type 1 variant circulating in the former Soviet Union.

The HIV-1 subsubtype A1 epidemic of the former Soviet Union (FSU) was caused by an A1 variant apparently derived from a single introduction event. We identified an A1 variant highly related to the A1 lineage circulating in the FSU in a patient from Conakry, Republic of Guinea, who was diagnosed with HIV-1 when he moved to Italy in 2002. The most probable route of infection was two blood transfusions received in his country of origin in 1998.

Association between serum values of C-reactive protein and cytokine production in whole blood of patients with type 2 diabetes.

Diabetes mellitus accelerates atherosclerotic processes, and it is known that inflammation plays a key role in atherosclerosis. The aim of the present study was to evaluate in patients with Type 2 diabetes whether serum levels of CRP (C-reactive protein) are associated with cytokine production in whole blood. A total of 89 outpatients with Type 2 diabetes were enrolled, and blood pressure, body mass index, fasting blood glucose, glycated haemoglobin, cholesterol, triacylglycerols (triglycerides) and hs-CRP (high-sensitivity CRP) were measured.

Vpr and HIV-1 disease progression: R77Q mutation is associated with long-term control of HIV-1 infection in different groups of patients.

Background: Vpr (viral protein R) is a 96 amino acids soluble protein that is expressed late during viral replication. Recent studies have focused on the role of a mutation at position 77 that might be associated with the condition of long-term non-progression, but data are still controversial.

Patients And Methods: Fifteen long-term non-progressors (LTNP), 19 therapy-naive HIV-1-infected patients with progressive disease (Pr), 23 HIV-1-infected patients receiving sub-optimal therapy with dual nucleoside [nucleoside reverse transcriptase inhibitor (NRTI)] therapy but efficiently controlling viral replication (STP) and 19 antiretroviral therapy multi-experienced patients with actively replicating virus (MEP) were analysed.

HIV-1 subtypes and circulating recombinant forms (CRFs) from HIV-infected patients residing in two regions of central and southern Italy.

A total of 347 pol gene sequences from 88 Tuscan and 259 Apulian subjects (including 52 non-Italians and 9 children) were analyzed phylogenetically. Forty-four (12.6%) non-B subtypes were found, including 3.