Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-α, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats. Copyright©2011 the authors.Instituto de Salud Carlos III (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), the Spanish Ministry of Science and Innovation (BFU2007-66008 to R.F-C., SAF2009-08233 to J.J.L., and Juan de la Cierva contracts to J.L.R. and C.T.-Z.), Junta de Andalucía (P07-CVI- 02854, P06-CVI-02392), Comunidad Autónoma de Madrid, Fundación Ramón Areces, and Fondo Europeo de Desarrollo RegionalPeer Reviewe

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Fecha de la aprobación : 1746Sign. : *4, A-D4, E2Notas a pie de pág. y reclamosInicial orlada y grab. xil. en p. [3], p. 1 y final del text

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington’s disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-_, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats

Instrucción de alcaldes ordinarios, que comprehende las obligaciones de éstos, y del Amotacen, conforme a las leyes de Castilla, ...

Sign. : []4, B-E4, F2Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2009-201

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Breue historia de la Villa de Villafranca del Cid en el reyno de Valencia y del hallazgo prodigioso de N. Señora del Losas ...

Copia digital. España : Ministerio de Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

Oracion panegirica de S. Bernardo de Alzira [Texto impreso] ... contra la plaga de Langosta ...

Sign. : []3, *3, A-C4, D1Letras iniciales decoradas y frisos tip. decorativosApostillas marginales y reclamo

Historia de la prodigiosissima imagen de Nuestra Señora del Niño Perdido : venerada en el ... colegio de Jesus de Nazareno de Agustinos Descalzos, en la Villa de Caudièl ... ; añadese ... la vida del ... Hermano Juan de la Virgen del Niño Perdido

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Apologia contra los Diarios de los Literatos de España : sobre los articulos XII. XIII y XIV del Tomo II y I del Tomo III

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Novel loci and Mapuche genetic ancestry are associated with pubertal growth traits in Chilean boys

Puberty is a complex developmental process that varies considerably among individuals and populations. Genetic factors explain a large proportion of the variability of several pubertal traits. Recent genome-wide association studies (GWAS) have identified hundreds of variants involved in traits that result from body growth, like adult height. However, they do not capture many genetic loci involved in growth changes over distinct growth phases. Further, such GWAS have been mostly performed in Europeans, but it is unknown how these findings relate to other continental populations. In this study, we analyzed the genetic basis of three pubertal traits; namely, peak height velocity (PV), age at PV (APV) and height at APV (HAPV). We analyzed a cohort of 904 admixed Chilean children and adolescents with European and Mapuche Native American ancestries. Height was measured on roughly a 6−month basis from childhood to adolescence between 2006 and 2019. We predict that, in average, HAPV is 4.3 cm higher in European than in Mapuche adolescents (P = 0.042), and APV is 0.73 years later in European compared with Mapuche adolescents (P = 0.023). Further, by performing a GWAS on 774, 433 single-nucleotide polymorphisms, we identified a genetic signal harboring 3 linked variants significantly associated with PV in boys (P <5×10−8). This signal has never been associated with growth-related traits