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

Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva--TRELONG).

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based "Treviso Longeva"--TRELONG Study from Italy (n = 668, age range 70-105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose-response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females

Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 Variations Does Not Impact Alcohol Dependence Disorder Features

We assessed a set of biological (HDL, LDL, SGOT, SGPT, GGT, HTc, Hb and T levels) and psychometric variables (investigated through HAM-D, HAM-A, GAS, Liebowitz Social Anxiety Scale, Mark & Mathews Scale, Leyton scale, and Pilowski scale) in a sample of 64 alcohol dependent patients, at baseline and after a detoxification treatment. Moreover, we recruited 47 non-consanguineous relatives who did not suffer alcohol related disorders and underwent the same tests. In both groups we genotyped 11 genetic variations (rs1800587; rs3087258; rs1799724; 5-HTTLPR; rs1386493; rs1386494; rs1487275; rs1843809; rs4570625; rs2129575; rs6313) located in genes whose impact on alcohol related behaviors and disorders has been hypothesized (IL1A, IL1B, TNF, 5-HTTLPR, TPH2 and HTR2A). We analyzed the epistasis of these genetic variations upon the biological and psychological dimensions in the cases and their relatives. Further on, we analyzed the effects of the combined genetic variations on the short – term detoxification treatment efficacy. Finally, being the only not yet investigated variation within this sample, we analyzed the impact of the rs6313 alone on baseline assessment and treatment efficacy. We detected the following results: the couple rs6313 + rs2129575 affected the Leyton -Trait at admission (p = 0.01) (obsessive-compulsive trait), whilst rs1800587 + 5-HTTLPR impacted the Pilowski test at admission (p = 0.01) (hypochondriac symptoms). These results did not survive Bonferroni correction (p ≤ 0.004). This lack of association may depend on the incomplete gene coverage or on the small sample size which limited the power of the study. On the other hand, it may reflect a substantial absence of relevance of the genotype variants toward the alcohol related investigated dimensions. Nonetheless, the marginal significance we detected could witness an informative correlation worth investigating in larger samples

A polymorphic variant of the insulin-like growth factor 1 (IGF-1) receptor correlates with male longevity in the Italian population: a genetic study and evaluation of circulating IGF-1 from the "Treviso Longeva (TRELONG)" study

<p>Abstract</p> <p>Background</p> <p>An attenuation of the insulin-like growth factor 1 (IGF-1) signaling has been associated with elongation of the lifespan in simple metazoan organisms and in rodents. In humans, IGF-1 level has an age-related modulation with a lower concentration in the elderly, depending on hormonal and genetic factors affecting the IGF-1 receptor gene (<it>IGF-1R</it>).</p> <p>Methods</p> <p>In an elderly population from North-eastern Italy (<it>n </it>= 668 subjects, age range 70–106 years) we investigated the <it>IGF-1R </it>polymorphism G3174A (<it>rs2229765</it>) and the plasma concentration of free IGF-1. Frequency distributions were compared using χ²-test "Goodness of Fit" test, and means were compared by one-way analysis of variance (ANOVA); multiple regression analysis was performed using JMP7 for SAS software (SAS Institute, USA). The limit of significance for genetic and biochemical comparison was set at α = 0.05.</p> <p>Results</p> <p>Males showed an age-related increase in the A-allele of <it>rs2229765 </it>and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between <it>rs2229765 </it>genotype and IGF-1 in the females.</p> <p>Conclusion</p> <p>These findings confirm the importance of the <it>rs2229765 </it>minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found.</p

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

Interleukin-1α, interleukin-1β and tumor necrosis factor-α genetic variants and risk of dementia in the very old: Evidence from the "monzino 80-plus" prospective study

The association among single nucleotide polymorphisms in inflammatory genes as interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) and dementia has been explored mostly in Alzheimer's disease, while few data addressing their association with dementia in very old people are available. We performed a prospective, door-to-door population-based study of 80 years or older residents in eight municipalities of Varese province, Italy (the Monzino 80-plus study). No difference was found by a cross-sectional approach comparing IL-1α rs1800587, IL-1β rs3087258 and TNF-α rs1799724 genotypic and allelic frequencies between those affected and not affected by dementia. After a 5-year follow-up, the elderly carriers of T-allele of TNF-α rs1799724 were at an increased risk of dementia (p=0.03). This association was no more significant adjusting for the apolipoprotein E epsilon-4 allele (APOE-ε4, p=0.26), which was an independent predictor of dementia onset (p=0.0002). In short, in this Italian population of oldest olds, dementia was associated to the APOE-ε4 allele only. © 2011 American Aging Association

Association study to evaluate the serotonin transporter and apolipoprotein E genes in frontotemporal lobar degeneration in Italy

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder characterized by behavioral and language disturbances. We performed a case-control association study in the Italian population to assess the relevance for FTLD genetic susceptibility of the serotonin (5-HT) transporter gene-linked polymorphic region [rs4795541, alias short (S)/long (L)] an in/del polymorphism of the promoter region of the gene coding for the 5-HT transporter (SLC6A4). This functional polymorphism was reported to influence the SLC6A4 transcription rate, with the S-allele having a two-fold reduced efficiency. We collected 225 independent subjects (74 sporadic FTLD and 151 age-matched healthy controls, CT) that were genotyped for the rs4795541, the SLC6A4 single nucleotide polymorphisms (SNP) rs25531 and rs6354, and the apolipoprotein E (APOE) allelic variants. A significant correlation [P = 0.018, OR (95% CI): 2.1 (1.1-3.9)] between rs4795541 S-allele presence and FTLD susceptibility was found. In summary, the rs4795541 might be important for FTLD susceptibility in the Italian population. © 2008 The Japan Society of Human Genetics and Springer

Interleukin-1 alpha and beta, TNF-alpha and HTTLPR gene variants study on alcohol toxicity and detoxitication outcome

Genetic factors may influence the liability to treatment outcome and medical complications in alcoholism. In the present study we investigated the IL-1A rs 1800587, IL-1B rs3087258, TNF-alpha rs 1799724 and the HTTLPR variants in a sample of 64 alcohol dependents and 47 relatives versus a set of clinical parameters and outcome measures. Alcohol dependents had a less favorable clinical profile compared to relatives (higher cholesterol, triglycerides, glucose, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, gamma-glutamyltransferase). After detoxification, all clinical indexes improved and hepatic enzyme levels were similar in alcohol dependents and relatives, except for the GGT that remained significantly higher in alcohol dependents. Alcoholic depressive and anxiety scores were significantly reduced after detoxification. IL-1A, IL- 1B, TNF-alpha and HTTLPR variants were not associated with any baseline clinical index or change after detoxification. In our sample IL-1A, IL-1B, TNF-alpha and HTTLPR do not appear as liability factors for alcohol toxicity or detoxification outcome, however the small sample size may influence the observed results. (c) 2006 Published by Elsevier Ireland Ltd