Enfermedad de Parkinson por mutaci��n vasca de la dardarina (LRRK2): estudio epidemiol��gico, cl��nico y gen��tico

149 p.

Diversidad genética de polimorfismos autos��micos en poblaciones africanas

El continente africano es la fuente de todos los seres humanos anat��micamente modernos, que m��s tarde se dispersaron por todo el planeta. ��frica posee el mayor nivel de variaci��n genética, por lo que es una regi��n de inter��s a estudiar. En este trabajo se ha analizado como se distribuye la variabilidad genética en ��frica con cada uno de los polimorfismos estudiados, polimorfismos de nucle��tido simple (SNP), grupos sangu��neos y microsat��lites (STR) y se ha comparado la informaci��n que ofrece cada tipo de marcador. Se observa una diferenciaci��n sobre todo de las familias Khoi-San y afroasi��ticos pero con diferencias seg��n que tipo de polimorfismo que se ha estudiado. En general la selecci��n natural parece haber afectado de forma similar a SNPs de genes codificantes y a grupos sangu��neos.

��Reemplazo demogr��fico en el Neol��tico europeo? El punto de vista de la Genética

[ES] El trabajo realiza una aproximaci��n a la situaci��n actual de los estudios de ADN antiguo humano en Europa, recopilando los datos de los individuos analizados hasta 2013 (n=700), a modo de s��ntesis interpretativa continental y regional de los territorios para los cuales se han obtenido resultados significativos (Centroeuropa, Cornisa Cant��brica, Mediterr��neo occidental, Escandinavia-B��ltico-Rusia y Alpes orientales). Las hip��tesis se expresan en t��rminos de continuidad o discontinuidad genética entre los grupos humanos habitantes de un territorio, centradas en la problem��tica de la neolitizaci��n, en una horquilla cronocultural del Paleol��tico superior a la Edad del Bronce. Los resultados se resumen en (1) una preponderancia del clado mitocondrial U para muestras preneol��ticas; (2) la posibilidad de una intrusi��n d��mica en una fase inicial de la neolitizaci��n centroeuropea -tipo N1a, con p��rdida posterior de ese haplogrupo mitocondrial-; (3) la evidencia del proceso neolitizador como heterog��neo y con diferente impacto a escala regional; (4) una estabilizaci��n del acervo gen��tico europeo actual como resultado de eventos postneol��ticos; y (5) las posibilidades anal��ticas de la genética aplicada a las poblaciones antiguas como un instrumento de gran inter��s, observ��ndose la necesidad de realizar m��s anal��ticas con recorrido diacr��nico.

Regulaci��n de las GTPasas de la familia Ras y la viabilidad de neuronas dopamin��rgicas en respuesta a la se��alizaci��n purin��rgica

158 p.

Morphofunctional changes in a rat model of Parkinson's disease - Effects of neurotrophic factors administration

255 p.

Epitope mapping of antibodies to alpha-synuclein in LRRK2 mutation carriers, idiopathic Parkinson disease patients, and healthy controls

Alpha-synuclein (Snca) plays a major role in Parkinson disease (PD). Circulating anti-Snca antibodies has been described in PD patients and healthy controls, but they have been poorly characterized. This study was designed to assess the prevalence of anti-Snca reactivity in human subjects carrying the LRRK2 mutation, idiopathic PD (iPD) patients, and healthy controls and to map the epitopes of the anti-Snca antibodies. Antibodies to Snca were detected by ELISA and immunoblotting using purified recombinant Snca in plasma from individuals carrying LRRK2 mutations (104), iPD patients (59), and healthy controls (83). Epitopes of antibodies were mapped using recombinant protein constructs comprising different regions of Snca. Clear positive anti-Snca reactivity showed no correlation with age, sex, years of evolution, or the disability scores for PD patients and anti-Snca reactivity was not prevalent in human patients with other neurological or autoimmune diseases. Thirteen of the positive individuals were carriers of LRRK2 mutations either non-manifesting (8 out 49 screened) or manifesting (5 positive out 55), three positive (out of 59) were iPD patients, and five positive (out of 83) were healthy controls. Epitope mapping showed that antibodies against the N-terminal (a.a. 1-60) or C-terminal (a.a. 109-140) regions of Snca predominate in LRRK2 mutation carriers and iPD patients, being N122 a critical amino acid for recognition by the anti-C-terminal directed antibodies. Anti-Snca circulating antibodies seem to cluster within families carrying the LRRK2 mutation indicating possible genetic or common environmental factors in the generation of anti-Snca antibodies. These results suggest that case-controls' studies are insufficient and further studies in family cohorts of patients and healthy controls should be undertaken, to progress in the understanding of the possible relationship of anti-Snca antibodies and PD patholog

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

Estudio de la etiolog��a genética de la insuficiencia ov��rica primaria (POI): genes FMR1 Y FMR2

243 p.

Uros, genética, ind��genas y colonos. A prop��sito de la Neolitizaci��n de Europa

El presente trabajo se ha preparado en el seno de los intereses de los proyectos de investigaci��n: HAR2011-26364 ���Las Comunidades humanas de la alta Cuenca del Ebro en la Transici��n Pleistoceno-Holoceno��� del Ministerio de Ciencia e Innovaci��n y CGL2009-12703-C03-03 ���Geolog��a, geocronolog��a y paleobiolog��a de los Yacimientos de la Sierra de Atapuerca��� del Ministerio de Educaci��n y Ciencia. As�� mismo se encuadra en el trabajo del Grupo de Investigaci��n en Prehistoria de la Universidad del Pa��s Vasco (UPV/EHU) IT-288-07/ UFI 11-09.

Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease

Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.

Caracter��sticas neuropsicol��gicas de pacientes con Enfermedad de Parkinson y portadores asintom��ticos de la mutaci��n R1441G en el gen LRRK2

238 p.

Inserciones Alu y heterogeneidad genética de la poblaci��n gitana del Pa��s Vasco

[ES] En este trabajo se ha analizado un grupo de 6 inserciones Alu autos��micas (ACE, APO, PV92, TPA25, FXIIIB y D1) en una muestra de 56 individuos de etnia gitana residentes en el Pa��s Vasco, con el objetivo de estimar la intensidad de los procesos de microdiferenciaci��n experimentados por esta poblaci��n y su parentesco gen��tico con otras poblaciones europeas y asi��ticas. Las inserciones Alu polim��rficas son unos marcadores muy ��tiles en los estudios de evoluci��n humana, entre otras razones porque se conoce su estado ancestral, que es la ausencia de inserci��n y porque se producen por un ��nico evento mutacional. Son por ello particularmente interesantes para analizar la heterogeneidad genética de poblaciones originarias de diferentes continentes.