alpha-synuclein and Craniocerebral-Trauma

Parkinson's disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.

Topics: Aging; alpha-Synuclein; Craniocerebral Trauma; Environmental Exposure; Genetic Predisposition to Disease; Herbicides; Humans; Nerve Tissue Proteins; Parkinson Disease; Smoking; Synucleins

To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk.. Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury.. Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction = 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03).. While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Case-Control Studies; Cohort Studies; Craniocerebral Trauma; Female; Genetic Variation; Humans; Male; Microsatellite Repeats; Middle Aged; Neurodegenerative Diseases; Parkinson Disease; Prospective Studies

Head trauma (HT) is emerging as an event anticipating onset of neurodegenerative disorders. However, the potential contribution of HT in young-onset cases (YOPD, age at onset < 50) of Parkinson's disease (PD) has not been examined yet. Here, we systematically assessed HT history in PD patients to estimate the risk associated, especially in terms of age of onset, and define the correlations with the clinical-biochemical profile. The Brain Injury Screening Questionnaire (BISQ) was administered to 94 PD patients (31 with YOPD, known monogenic forms excluded) and 70 controls. HT history was correlated with motor and non-motor scores in all patients, and to CSF biomarkers of neurodegeneration (α-synuclein, amyloid-β42, total and phosporiled-181 tau, lactate, CSF/serum albumin) into a subgroup. HT increased the risk for both PD and YOPD. In PD patients, but not in those with YOPD, the number of HTs directly correlated with CSF total-tau levels. No other correlations resulted between HT and clinical parameters. Sport-related HT was a specific risk factor for YOPD; conversely, the prolonged sporting life represented a protective factor. HTs can favor PD onset, even as YOPD. Sport-related HT resulted a risk factor for YOPD, although the longer sporting practice delayed PD onset, protecting from YOPD. Tauopathy may underlie the overall association between HT and PD. Additional mechanisms could be instead implicated in HT contribution to YOPD onset.

Topics: Age of Onset; alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Craniocerebral Trauma; Humans; Middle Aged; Parkinson Disease

Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated.. From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated.. Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant.. Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Craniocerebral Trauma; Female; Gene-Environment Interaction; Genetic Variation; Humans; Male; Middle Aged; Parkinson Disease; Risk Factors

To evaluate the association between head injury and Parkinson's disease (PD), focusing on the timing of head injury, and to explore potential interactions between head injury and genetic factors in PD etiology.. The analysis included 507 PD cases and 1330 controls, all non-Hispanic Whites. Head injury was retrospectively asked, and genotyping was performed mainly as part of a previous GWAS.. We found a positive association between head injury and PD risk. Compared with no previous head injury, the odds ratio (OR) was 1.39 (95% confidence interval [CI]: 1.00, 1.94) for one and 2.33 (95% CI: 1.25, 4.35) for two or more head injuries (P for trend = 0.0016). We further found that the higher risk was largely attributed to head injuries before age 30. Compared with no previous head injury, the OR was 2.04 (95% CI: 1.33, 3.14) for head injury that occurred before age 18, 1.39 (95% CI: 0.81, 2.36) for head injury between ages 18-<30, and 1.04 (95% CI: 0.58, 1.87) for head injury that occurred at age 30 or older (P for trend = 0.001). Exploratory interaction analyses showed a significant interaction between head injury and a SNP at the RBMS3 locus (rs10510622, uncorrected P = 0.0001). No interaction was found with GWAS tag SNPs at or near the MAPT, SNCA, LRRK2, and HLA loci.. Our study suggests that head injury early in life may be an important risk factor for PD. The potential interaction with RBMS3 needs confirmation.

Topics: Adult; Age Factors; Aged; alpha-Synuclein; Craniocerebral Trauma; Female; Gene-Environment Interaction; Genetic Association Studies; Genotype; HLA-A Antigens; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Middle Aged; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Retrospective Studies; Risk Factors; tau Proteins

Topics: alpha-Synuclein; Craniocerebral Trauma; Female; Gene-Environment Interaction; Humans; Male; Parkinson Disease