α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting αSyn reverted the degenerative phenotype under both basal and induced stress conditions, indicating a treatment strategy for PD and other synucleinopathies. Furthermore, mutant neurons showed disrupted synaptic connectivity and widespread transcriptional alterations in genes involved in synaptic signaling, a number of which have been previously linked to mental disorders, raising intriguing implications for potentially converging disease mechanisms.

During development of the spinal cord, Prox1 controls the balance between proliferation and differentiation of neural progenitor cells via suppression of Notch1 gene expression.

Isw1p and Isw2p are budding yeast homologs of the Drosophila ISWI chromatin-remodeling ATPase. Using indirect-end-label and chromatin immunoprecipitation analysis, we show both independent and cooperative Isw1p-and Isw2p-mediated positioning of short nucleosome arrays in gene-regulatory elements at a variety of transcription units in vivo. We present evidence that both yeast ISWI complexes regulate developmental responses to starvation and that for Isw2p, recruitment by different DNA-binding proteins controls meiosis and haploid invasive growth.

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Control of cell cycle progression/exit and differentiation of neuronal precursors is of paramount importance during brain development. BM88 is a neuronal protein associated with terminal neuron-generating divisions in vivoThe formation of the nervous system is governed by a delicate balance between cell proliferation, subsequent cell cycle withdrawal, and differentiation to distinctive neuronal phenotypes (1, 2). Current observations have highlighted the existence of mechanisms coupling cell cycle exit and differentiation as well as functional cross-talk between intrinsic factors controlling these two mechanisms. A number of key factors regulating cell cycle progression have been implicated in cell fate determination and differentiation of neuronal precursors, whereas specification-and/or differentiation-inducing molecules are beginning to emerge as cell cycle regulators (3-6). However, there are still important questions regarding the timing control of the proliferation/differentiation switch that remain unanswered.In the central nervous system, control of cell cycle progression plays an essential role in the generation of the appropriate number of neurons and the formation of functional neuronal circuits. When a neuronal progenitor is committed to undergo differentiation, it exits from the G 1 phase of the cell cycle and enters into an irreversible quiescent state referred to as G 0 . The tumor suppressor proteins p53 and pRb 6 are central regulators of this progression (7). p53, when activated, causes G 1 arrest at the G 0 restriction point by inducing expression of p21 and consequent inhibition of D-type cyclins and related cyclin-dependent kinases (8 -10), thus preventing phosphorylation of pRb (7). Under these conditions, hypophosphorylated pRb associates with the E2F family of transcription factors, thus impairing their ability to transactivate genes required for cell cycle progression (11). As a consequence cells do not progress through the G 1 -to-S phase transition. Several studies have indicated that a critical event associated with cell cycle withdrawal and differentiation both in neuronal and non-neuronal cells is the cellular compartmentalization of cyclin D1, which shifts from a predominantly nuclear localization to cytoplasmic sequestration

Transcriptome analysis by RNA-seq technology allows novel insights into gene expression and regulatory networks in health and disease. To better understand the molecular basis of renal fibrosis, we performed RNA-seq analysis in the Unilateral Ureteric Obstruction (UUO) mouse model. We analysed sham operated, 2-and 8-day post-ligation renal tissues. Thousands of genes with statistical significant changes in their expression were identified and classified into cellular processes and molecular pathways. Many novel protein-coding genes were identified, including critical transcription factors with important regulatory roles in other tissues and diseases. Emphasis was placed on long non-coding RNAs (lncRNAs), a class of molecular regulators of multiple and diverse cellular functions. Selected lncRNA genes were further studied and their transcriptional activity was confirmed. For three of them, their transcripts were also examined in other mouse models of nephropathies and their up-or downregulation was found similar to the UUO model. In vitro experiments confirmed that one selected lncRNA is independent of TGFβ or IL1b stimulation but can influence the expression of fibrosis-related proteins and the cellular phenotype. These data provide new information about the involvement of protein-coding and lncRNA genes in nephropathies, which can become novel diagnostic and therapeutic targets in the near future.Chronic kidney disease (CKD) is a frequent condition, causing severe long-term effects with devastating personal and societal consequences 1-3 . There is a need for novel approaches to prevent the decline in renal function during progression of CKD. Considering that the structural basis for this decline is the development of fibrosis, we believe that understanding the molecular basis of renal fibrosis, could offer valuable insights for the improvement of monitoring techniques and therapeutic interventions.To address this question, we combined a systems biology approach in animal models for renal fibrosis, focusing on (but not limited to) the unilateral ureteric obstruction (UUO) model 4,5 . We identified the full transcriptome of renal tissue, using the RNA-seq methodology, during early and late time intervals of kidney fibrosis. This methodology allows the identification of new protein-coding transcripts and novel non-coding RNA transcripts 6 . This is an exciting new direction, since about 75% of the mammalian genome (including human) is transcribed but not translated into proteins, and certain types of non-coding RNAs, especially long non coding RNAs (lncRNAs), play critical regulatory roles in many biological processes 7,8 . However, no data are currently available on the full transcriptome analysis of renal tissue from the UUO model in mice. By performing whole transcriptome sequencing and thorough bioinformatics analysis, we gathered novel information regarding up-regulated and down-regulated genes, pathways and biological processes, and we made lists of differentially expressed genes not suspected so far to be i...

Non-technical summary Neuronal plasticity refers to the ability of the brain to change in response to different experiences. Plasticity varies between people, but it is not known how much of this variability is due to differences in their genes. In humans, plasticity can be probed by a protocol termed paired associative stimulation and the changes in the motor system that are brought about by such stimulation are thought to be due to strengthening synapses which connect different neurons. We examined pairs of sisters which were either genetically identical (monozygotic) or different (dizygotic). We found that the variability within the monozygotic sister pairs was less than the variability within the dizygotic sister pairs. That plasticity in human motor cortex is in a substantial part genetically determined may be relevant for motor learning and neurorehabilitation, such as after stroke.Abstract Brain plasticity refers to changes in the organization of the brain as a result of different environmental stimuli. The aim of this study was to assess the genetic variation of brain plasticity, by comparing intrapair differences between monozygotic (MZ) and dizygotic (DZ) twins. Plasticity was examined by a paired associative stimulation (PAS) in 32 healthy female twins (9 MZ and 7 DZ pairs, aged 22.6 ± 2.7 and 23.8 ± 3.6 years, respectively). Stimulation consisted of low frequency repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with a single pulse transcranial magnetic stimulation (TMS) for activation of the abductor pollicis brevis muscle (APB). Corticospinal excitability was monitored for 30 min following the intervention. PAS induced an increase in the amplitudes of the motor evoked potentials (MEP) in the resting APB, compared to baseline. Intrapair differences, after baseline normalization, in the MEP amplitudes measured at 25-30 min post-intervention, were almost double for DZ (1.25) in comparison to MZ (0.64) twins (P = 0.036). The heritability estimate for brain plasticity was found to be 0.68. This finding implicates that genetic factors may contribute significantly to interindividual variability in plasticity paradigms. Genetic factors may be important in adaptive brain reorganization involved in motor learning and rehabilitation from brain injury.

Tissue damage following injury leads to inflammation and fibrosis. To understand the molecular mechanisms and the proteins involved in the fibrotic process, we used the well-established unilateral ureteric obstruction rat model and we analyzed the alterations at early and late time intervals using a classical proteomic approach. Data analysis demonstrates a correlation between calreticulin up-regulation and progression of fibrosis. Calreticulin is involved in Ca++ homeostasis but has not been previously implicated in animal models of fibrosis. Proteomic analysis consistently revealed up-regulation of calreticulin in both early and late time intervals. These findings were further confirmed by biochemical and morphological approaches. Next, animal models of lung fibrosis (bleomycin-induced) and heart fibrosis (desmin-null) were examined. In the lung model, calreticulin expression was up-regulated from early time intervals, whereas in the heart model no change in the expression of calreticulin was observed. In addition, TGF-beta, a well known major contributing factor in several fibrotic processes, was found to up-regulate calreticulin in cultured human proximal tubule epithelial cells. The above observations suggest that calreticulin might be involved in fibrotic processes; however the mechanism(s) underlying its possible involvement are yet unresolved.