京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20820号 / 生博第389号 / 新制||生||51(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 米原 伸, 教授 垣塚 彰, 教授 HEJNA James / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-03-21T11:41:24Z No. of bitstreams: 1 ClarissaLoureiroCampeloBezerra_TESE.pdf: 6936560 bytes, checksum: 72a397096dabf519d649a5db63d55327 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-03-22T15:43:33Z (GMT) No. of bitstreams: 1 ClarissaLoureiroCampeloBezerra_TESE.pdf: 6936560 bytes, checksum: 72a397096dabf519d649a5db63d55327 (MD5) / Made available in DSpace on 2018-03-22T15:43:33Z (GMT). No. of bitstreams: 1 ClarissaLoureiroCampeloBezerra_TESE.pdf: 6936560 bytes, checksum: 72a397096dabf519d649a5db63d55327 (MD5) Previous issue date: 2017-03-14 / Crescentes evidencias indicam que a susceptibilidade gen?tica contribui para a etiologia da doen?a de Parkinson espor?dica (DP). Varia??es gen?ticas no gene SNCA, respons?vel pela codifica??o da alfa-sinucle?na, foram bem estabelecidas atrav?s de estudos de linkage e GWAS. Estudos em todo o mundo encontraram associa??o positiva com polimorfismos de nucleot?deo ?nico (SNPs) no gene SNCA e o aumento do risco para DP. Al?m disto, varia??es no SNCA podem influenciar caracter?sticas ou fen?tipos da DP espor?dica. Este estudo teve como objetivo investigar associa??es entre os SNPs no gene SNCA e a sintomatologia motora e n?o-motora da DP em uma popula??o brasileira. 206 sujeitos (grupo DP= 105 e grupo controle= 101) participaram do estudo. Os pacientes com DP foram recrutados no ambulat?rio de neurologia do Hospital Onofre Lopes, na cidade de Natal (RN). Foram utilizados question?rios e escalas para avaliar o hist?rico de sa?de, fatores ambientais, aspectos motores (Hoehn & Yarh e Unified Parkinson?s Disease Rating Scale), funcionais (Schwab & England), cognitivos (Bateria de Avalia??o Frontal e Mini-Exame do Estado Mental) e emocionais (Invent?rio de Depress?o de Beck e Inventario de Ansiedade de Beck) dos participantes. Tamb?m foi coletada uma amostra de sangue para a realiza??o da extra??o do DNA e posterior genotipagem dos SNPs rs11931074, rs356219, rs2583988, rs2736990. Quanto a avalia??o cl?nica, o grupo DP apresentou comprometimento motor de moderado a severo associado a uma moderada redu??o da capacidade funcional. Os d?ficits cognitivos foram mais presentes nos sujeitos com baixa escolariza??o. Os sintomas depressivos e ansiosos foram evidenciados com maior frequ?ncia e gravidade no grupo DP. Os dados da genotipagem mostraram todos os SNP mais frequentes no grupo DP, e a associa??o dos SNPs rs356219, rs2583988, rs2736990 aumentando o risco para DP foi confirmada. Tamb?m foi encontrada uma associa??o dos alelos de risco com a DP de in?cio precoce. T-rs2583988, G-rs356219 e C-2736990 foram significativamente mais frequentes nos pacientes com altera??es cognitivas quando comparados aos controles com a mesma condi??o. Al?m disto, a presen?a de altera??es cognitivas foi mostrou-se um fator preditivo para a DP em um modelo de regress?o log?stica. Este estudo ? o primeiro a demonstrar a associa??o de polimorfismos no gene SNCA em uma popula??o da Am?rica do Sul. / Increasing evidence indicate that genetic susceptibility contributes to the etiology of sporadic Parkinson?s Disease (PD). Genetic variations in SNCA gene, which encodes alpha-synuclein protein, are already well established in linkage and GWAS studies. Worldwide studies have find positive association of single nucleotide polymorphism (SNP) in SNCA and the increase risk for PD. In addition, variants in SNCA can influence individual traits or phenotypes of sporadic PD. The present study investigated associations between SNPs in SNCA gene and motor and non-motor symptoms of PD in a Brazilian population. 206 subjects (PD group= 105 and Control group = 101) participated in this study. The patients with PD were recruited from the neurology clinic of Onofre Lopes University Hospital, in Natal (RN, Brazil). We used questionnaires and scales to evaluate the healthy history, environmental factors, motor (Hoehn & Yarh e Unified Parkinson?s Disease Rating Scale), functional (Schwab & England), cognitive (Frontal Assessment Battery and Mini Mental State Examination) and emotional (Beck Depression Inventory and Beck Anxiety Inventory) aspects of the subjects. We also collected a blood sample to DNA extraction and genotyping of SNPs rs11931074, rs356219, rs2583988 and rs2736990. Regarding clinical assessment, the PD group presented motor impairment associated to a moderate decrease of functional capacity. The cognitive impairments were more evident in individuals with low education. Depressive and anxiety symptoms had a higher frequency and severity in PD group. All SNPs were more frequent in PD patients (p<0.05), and the associations of SNPs rs2583988, rs356219 and rs2736990 with increased PD risk were confirmed. The G-rs356219 and C-rs2736990 alleles had a significant higher frequency in patients with early onset PD. T-rs2583988, G-rs356219 and C-2736990 risk alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. Furthermore, the presence of cognitive impairment was a predictor for PD in a logistic regression model. This study demonstrated for the first time an association of SNCA polymorphisms and PD in a South-American sample.

No description available.

Parkinson’s disease (PD) is a common neurodegenerative movement disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of aggregated alpha synuclein (aSyn). The disease often presents with early prodromal non-motor symptoms and later motor symptoms. Diagnosing PD based purely on motor symptoms is often too late for successful intervention, as a significant neuronal loss has already occurred. Furthermore, the lower prevalence of PD in females is not well understood, highlighting the need for a better understanding of the interaction between sex and aSyn, the crucial protein for PD pathogenesis. Here, we conducted a comprehensive phenotyping study in 1- to 5-month-old mice over- expressing human aSyn gene (SNCA) in a bacterial artificial chromosome (BAC-SNCA). We demonstrate a SNCA gene-dose-dependent increase of human aSyn and phosphorylated aSyn, as well as a decrease in tyrosine hy- droxylase expression in BAC-SNCA mice, with more pronounced effects in male mice. Phosphorylated aSyn was already found in the dorsal motor nucleus of the vagus nerve of 2-month-old mice. This was time-wise associated with significant gait altrations in BAC-SNCA mice as early as 1 and 3 months of age using CatWalk gait analysis. Furthermore, anxiety-related behavioral tests revealed an increase in anxiety levels in male BAC-SNCA mice. Finally, 5-month-old male BAC-SNCA mice exhibited a SNCA gene-dose-dependent elevation in energy expen- diture in automated home-cage monitoring. For the first time, these findings describe early-onset, sex- and gene- dose-dependent, aSyn-mediated disturbances in BAC-SNCA mice, providing a model for sex-differences, early- onset neuropathology, and prodromal symptoms of PD.