11 research outputs found
The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity
BACKGROUND Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein \textgreeka-synuclein (\textgreeka-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by \textgreeka-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA). OBJECTIVE The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. METHODS We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models including DJ-1 knockout (-/-) mice to investigate DJ-1 in dopaminergic degeneration. RESULTS We found that in PC12/TetOn cells overexpressing \textgreek{a}-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased \textgreek{a}-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of \textgreek{a}-syn (TAT-\textgreek{a}-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-\textgreek{a}-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain. CONCLUSION DJ-1 appears to have a protective role against dopaminergic degeneration triggered by \textgreek{a}-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD
A Novel Study and Meta-Analysis of the Genetic Variation of the Serotonin Transporter Promoter in the Italian Population Do Not Support a Large Effect on Alzheimer's Disease Risk
Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A ā G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk
Hydrogel-Based Nanocomposites and Mesenchymal Stem Cells: A Promising Synergistic Strategy for Neurodegenerative Disorders Therapy
Hydrogel-based materials are widely employed in the biomedical field. With regard to central nervous system (CNS) neurodegenerative disorders, the design of injectable nanocomposite hydrogels for in situ drug or cell release represents an interesting and minimally invasive solution that might play a key role in the development of successful treatments. In particular, biocompatible and biodegradable hydrogels can be designed as specific injectable tools and loaded with nanoparticles (NPs), to improve and to tailor their viscoelastic properties upon injection and release profile. An intriguing application is hydrogel loading with mesenchymal stem cells (MSCs) that are a very promising therapeutic tool for neurodegenerative or traumatic disorders of the CNS. This multidisciplinary review will focus on the basic concepts to design acellular and cell-loaded materials with specific and tunable rheological and functional properties. The use of hydrogel-based nanocomposites and mesenchymal stem cells as a synergistic strategy for nervous tissue applications will be then discussed
The Parkinson's Disease-Related Protein DJ-1 Protects Dopaminergic Neurons in vivo and Cultured Cells from Alpha-Synuclein and 6-Hydroxydopamine Toxicity
Background: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein ??-synuclein (??-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by ??-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA). Objective: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. Methods: We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration. Results: We found that in PC12/TetOn cells overexpressing ??-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased ??-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of ??-syn (TAT-??-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-??-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain. Conclusion: DJ-1 appears to have a protective role against dopaminergic degeneration triggered by ??-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD
Effects of SORL1 Gene on Alzheimer's Disease. Focus on Gender, Neuropsychiatric Symptoms and Pro-Inflammatory Cytokines
It was suggested that the gene encoding for sorLa, (SORL1) may affect
Alzheimerās disease (LOAD) through a female-specific mechanism. The aims
of this study were to confirm the role of gender in modulating the
association between SORL1 and LOAD and to ascertain the influence of
SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and
secretion of pro-inflammatory cytokines.
Ninety six outpatients with LOAD and 120 unrelated controls were
genotyped for APOE and three SNPs at the 5ā end of SORL1(intron 6): SNP
8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation
was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell
Scale for Depression in Dementia (CDDS). ELISPOT assays were used to
measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma)
production in peripheral blood mononuclear cell (PBMC) supernatant from
AD patients.
SORL1 SNPs were not associated with LOAD in overall sample. Instead the
G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype
(p=0.02) were associated with LOAD in the women subgroup. The TAA
haplotype was marginally protective in AD patients being associated with
lower BPSD scores (p=0.01). The same haplotype was also associated with
higher IL-1beta (p=0.01) production. These genetic effects were not
modified by APOE4 allele and controlled for illness duration and
treatment.
In conclusion, SORL1 does not appear to be a major risk factor for LOAD.
Its contribution could be underestimated in our small sample.
Sex-specific factors could modulate the association between SORL1 and
AD. The influence of SORL1 variants on production of inflammatory
cytokines warrants further investigation
Association of SORL1 Alleles with Late-Onset Alzheimerās Disease. Findings from the GIGAS_LOAD Study and Mega-Analysis
The pathophysiology of Alzheimerās disease (AD) is influenced by
sorting-protein related receptor (sorLa) that is less expressed in AD
patients. The gene encoding sorLa (SORL1) has been investigated as a
susceptibility factor for late-onset AD (LOAD) with conflicting results.
Our objectives were to confirm the association between SORL1 SNPs and
LOAD in two independent South-European centers and to perform a
mega-analysis of published samples. We analyzed three SORL1 SNPs (intron
6: rs668387; rs689021; rs641120) from the Greece-Italy Genetic
Association Study on late-onset AD (GIGAS_LOAD). Greek sample included
96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a
community-based sample is ongoing. 47 LOAD patients and 165 controls
were recruited until study endpoint. These samples and previously
published ones (Alzgene) were pooled as in a single study. A test for
trend was used to analyze genotype association. In the GIGAS_LOAD
sample no association was detected between SORL1 genotypes and LOAD.
Conversely all SNPs were associated with LOAD in mega-analysis based on
ordinal classification of genotypes (Armitageās test: p<0.001). Although
our analysis of pooled samples has positive results for the association
between SORL1 and AD, there is substantial heterogeneity across studies.
Thus further examination into SORL1 SNPs and the population is necessary
to determine the role of SORL1 in LOAD