Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

We have assessed the impact of a-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of a-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.Instituto de Investigaciones Bioquímicas de La Plat

Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

We have assessed the impact of a-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of a-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.Instituto de Investigaciones Bioquímicas de La Plat

Substituição de monensina sódica por bicarbonato de sódio em dietas de novilhas confinadas

The effects of replacing monensin with sodium bicarbonate in diets for confined heifers on weight gain (WG), dry matter intake (DMI), feed:gain ratio (FGR) and rumen fermentation parameters were evaluated. Fifity six heifers were utilized (Santa Gertrudis x Braunvieh). Diets were formulated with two levels of concentrate (50% and 80% concentrate) with sodium monensin or sodium bicarbonate. The DMI was higest in heifers with an intake of 80% concentrate. There was not difference when the same concentrate levels were evaluated in relation to the DMI. The heifers at 80% concentrate showed highest WG. There was no significant difference in relation to WG between monensin and bicarbonate treatments and levels concentrate proportions. There were significant effects regarding FGR between treatments. The heifers on 80% concentrate showed lowest FGR. In the evaluation of N-NH3, the highest values were observed, on the whole, at 80:20 diets in relation to 50:50 diets. In the additive use, the monensin on 80:20 diets promoted the highest values of N-NH3 at 1 for 9 hours after feed intake. In the values of ruminal pH, the bicarbonate increased the values on 50:50 at 6 for18 hours after feed intake, in relation to the 80:20 diet. In this case, it was concluded that the use of sodium bicarbonate in diets for confined finishing heifers is a viable option for the replacement of monensin sodium.Avaliaram-se os efeitos da substituição da monensina sódica pelo bicarbonato de sódio em dietas de novilhas em confinamento em relação ao desempenho animal, à conversão alimentar e ao parâmetro de fermentação ruminal. Foram utilizadas 56 novilhas mestiças, confinadas por 112 dias, submetidas a dietas com duas porcentagens de concentrado, 50% e 80% da matéria seca, com adição de monensina sódica ou bicarbonato de sódio, em fatorial 2x2. O volumoso utilizado para compor as dietas testadas foi composto de silagem de milho e cana-de-açúcar na proporção de 60:40, respectivamente. O nitrogênio amoniacal foi maior nos animais alimentos com dietas com alto grão. A monensina, na dieta 80:20, proporcionou maiores valores de nitrogênio amoniacal, uma e nove horas após o consumo da ração. O uso de bicarbonato promoveu os maiores valores de pH ruminal na dieta com 50% de concentrado, de seis a 18 horas após o consumo. Não houve efeito do aditivo sobre o desempenho animal. A alta inclusão de grãos na dieta propiciou aumento do desempenho animal e da eficiência alimentar. Conclui-se que o uso de bicarbonato de sódio em dietas para terminação de animais em confinamento é uma opção viável em substituição à monensina sódica para a manipulação da fermentação ruminal

Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease

With the advent of the genetic era in Parkinson’s disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein’s varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD. © 2021, The Author(s)