BackgroundParkinson's disease (PD) is a neurodegenerative pathology whose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release. DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too.Methodology/Principal FindingsThe present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to finding some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induced by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates.Conclusion/SignificanceDJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.

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The transcription rate of interleukin-6 (IL-6) can be reduced by the C-allele of a polymorphism (rs1800795) located in the 5′-flanking region of the IL-6 gene (NM_000600), and IL-6 plasma levels increase with age. We assembled an elderly Italian population ["The Treviso Longeva (Trelong) study", age range 70-106 years, n = 668 subjects] and assessed rs1800795 genotype and plasma IL-6 concentrations. The rs1800795 genotype was also assessed in an independent Italian study ("Milan" study, age range 70-96, n= 245 subjects). To verify an age-or sex-specific effect of rs1800795 genotype we compared people younger (70-85) and older (85+) than 85 years of age. We found a significant reduction in the frequency of rs1800795 C/C genotype in 85+ men from the Trelong study, while in the Milan study this data did not reach significance. However, considering the two studies together, the frequency of the rs1800795 C/C genotype was significantly lower in 85+ than in 70-85 males (4.0% and 10.7%, respectively), while it remained unchanged in females. As for IL-6 plasma levels, after a multivariate analysis to control for confounders, a correlation between age and plasma IL-6 concentrations was revealed (P <0.0001). An increase in circulating IL-6 levels in the entire 85+ group compared to the 70-85 group (P<0.05, Tukey′s test) was also noticed. We suggest a sex-specific pattern for genetic variability linked to inflammatory response and longevity, consistent with the age-related increase in IL-6.

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The genetic form of Alzheimer disease (FAD) accounts for about 5% of total Alzheimer disease (AD) cases, and the discovery of FAD-linked genes has shed new light on AD pathogenic mechanism. The presenilins genes (PSEN-1 and PSEN-2) carry the large majority of FAD-linked mutations. Here, we report an Italian kindred with FAD and PSEN-1 double mutation E318G+G394V that clearly cosegregates with the pathology. The E318G mutation has not an assessed pathogenic function, but some data have highlighted a role as a risk factor for AD in a predisposed familiar background. The G394V mutation was still described in association to an AD case with reported (but not demonstrated) familiar cosegregation. In an attempt to better characterize the biochemical effect of this double mutation, we assessed A beta(1-40) and A beta(1-42) concentrations in conditioned media from primary skin fibroblasts obtained from AD-affected and healthy family members. We did not find any modification of the A beta(1-42)/A beta(1-40) ratio, suggesting that this double mutation might be involved in early-onset AD etiopathogenesis by affecting a PSEN-1 function other than gamma-secretase activity.