Highlights d DM1 RNA-seq shows mis-splicing of neurotransmitter receptors along a severity gradient d Repeats >1,000 CTGs occur in all individuals; lengths correlate with mis-splicing d GRIP1 mis-splicing perturbs kinesin association and may alter synaptic trafficking d Expression changes suggest neuroinflammation and downregulation of neuronal genes
SummaryAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by motor neuron cell death. However, not all motor neurons are equally susceptible. Most of what we know about the surviving motor neurons comes from gene expression profiling; less is known about their functional traits. We found that resistant motor neurons cultured from SOD1 ALS mouse models have enhanced axonal outgrowth and dendritic branching. They also have an increase in the number and size of actin-based structures like growth cones and filopodia. These phenotypes occur in cells cultured from presymptomatic mice and mutant SOD1 models that do not develop ALS but not in embryonic motor neurons. Enhanced outgrowth and upregulation of filopodia can be induced in wild-type adult cells by expressing mutant SOD1. These results demonstrate that mutant SOD1 can enhance the regenerative capability of ALS-resistant motor neurons. Capitalizing on this mechanism could lead to new therapeutic strategies.
Many of estradiol’s behavioral effects are mediated, at least partially, via extra-nuclear estradiol signaling. Here, we investigated whether two estrogen receptor (ER) agonists, targeting ERα and G protein-coupled ER-1 (GPER-1), can promote rapid anorexigenic effects. Food intake was measured in ovariectomized (OVX) rats at 1, 2, 4, and 22h following subcutaneous (s.c.) injection of an ERα agonist (PPT; 0–200μg/kg), a GPER-1 agonist (G-1; 0–1600μg/kg), and a GPER-1 antagonist (G-36; 0–80μg/kg). To investigate possible cross-talk between ERα and GPER-1, we examined whether GPER-1 blockade affects the anorexigenic effect of PPT. Feeding was monitored in OVX rats that received s.c. injections of vehicle or 40μg/kg G-36 followed 30min later by s.c. injections of vehicle or 200μg/kg PPT. Selective activation of ERα and GPER-1 alone decreased food intake within 1h of drug treatment, and feeding remained suppressed for 22h following PPT treatment and 4h following G-1 treatment. Acute administration of G-36 alone did not suppress feeding at any time point. Blockade of GPER-1 attenuated PPT’s rapid (within 1h) anorexigenic effect, but did not modulate PPT’s ability to suppress food intake at 2, 4 and 22h. These findings demonstrate that selective activation of ERα produces a rapid (within 1h) decrease in food intake that is best explained by a non-genomic signaling pathway and thus implicates the involvement of extra-nuclear ERα. Our findings also provide evidence that activation of GPER-1 is both sufficient to suppress feeding and necessary for PPT’s rapid anorexigenic effect.
In the originally published version of this article, the authors concluded that the observed effects of SOD1 mutation were elicited in adult cells only. This statement was meant to summarize the results of this article. In light of other studies that have examined the morphology of motor neurons at early post-natal stages, the text referring to the effects of mutant SOD1 expression in adult cells has been modified. An expanded discussion and references have also been added to the manuscript. Specifically, these sentences: ''Enhanced regeneration of mutant SOD1 motor neurons only occurs in adult cells and is independent of ALS onset.'' ''Increased outgrowth only occurs in adult neurons and is independent of ALS symptoms.'' ''Figure 2. Enhanced outgrowth and branching of adult motor neurons from mutant SOD1 mice is specific to adult cells and independent of ALS onset.'' now read ''Enhanced regeneration of adult mutant SOD1 motor neurons is independent of ALS onset.'' ''Increased outgrowth in adult motor neurons is independent of ALS symptoms.'' ''Figure 2. Enhanced outgrowth and branching of adult motor neurons from mutant SOD1 mice is independent of ALS onset.'' The sentence ''In fact, the enhanced outgrowth and branching phenotypes only becomes apparent after the mouse is two months old (Figure 2D).'' has been deleted. Finally, the authors have expanded the discussion and added the references reported below.
RNA transport and local translation provide spatial control of gene expression, and RNA binding proteins (RBPs) act as critical adapters in this multi-step process. Muscleblind-like (MBNL) RNA binding proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and distal neurites through unknown mechanisms. We found that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα ; and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs also associate with these kinesins, implicating a motor-RBP specificity code. Live cell imaging and fractionation revealed that membrane anchoring is mediated through the unstructured carboxy-terminal tail of MBNL1. Both kinesin- and membrane-recruitment functions were reconstituted using MBNL-MS2 coat protein fusions. This approach, termed RBP Module Recruitment and Imaging (RBP-MRI), decouples RNA binding, kinesin recruitment, and membrane anchoring functions, while also establishing general strategies for studying multi-functional, modular domains of RBPs.
Background: Many students use laptops in the classroom to take notes; however, even when laptops are used for the sole purpose of taking notes they can negatively impact academic performance. Objective: The current study examined state-dependent effects, and the potential for a match in note taking and quiz taking methods to improve quiz performance. Method: Participants were placed into a congruent (take notes by hand and complete the quiz by hand or take notes using a laptop and complete an online quiz) or an incongruent condition (take notes by hand and take an online quiz or take notes using a laptop and complete the quiz by hand). Results: The results revealed that participants who took notes by hand performed better on the quiz overall, and better on conceptual questions, then students who took notes using a laptop. We failed to find evidence for state-dependent effects. Conclusions: The current study suggests that taking notes by hand may improve how students encode material, and result in higher quality external storage used by students when studying for quizzes. Teaching Implications: Reinforcing the notion that taking notes by hand may benefit quiz performance for lecture-style information and could improve student performance in class.
Myotonic dystrophy (dystrophia myotonica, DM) is caused by expanded CTG/CCTG microsatellite repeats, leading to multi-systemic symptoms in skeletal muscle, heart, gastrointestinal, endocrine, and central nervous systems (CNS), among others. For some patients, CNS issues can be as debilitating or more so than muscle symptoms; they include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Although transcriptomes from DM type 1 (DM1) skeletal muscle have provided useful insights into pathomechanisms and biomarkers, limited studies of transcriptomes have been performed in the CNS. To elucidate underlying causes of CNS dysfunction in patients, we have generated and analyzed RNA-seq transcriptomes from the frontal cortex of 21 DM1 patients, 4 DM type 2 (DM2) patients, and 8 unaffected controls. One hundred and thirty high confidence splicing changes were identified, most occurring exclusively in the CNS and not in skeletal muscle or heart. Mis-spliced exons were found in neurotransmitter receptors, ion channels, and synaptic scaffolds, and we identified an alternative exon in GRIP1 that modulates association with kinesins. Splicing changes exhibited a gradient of severity correlating with CTG repeat length, as measured by optical mapping of individual DNA molecules. All individuals studied, including those with modest splicing defects, showed extreme somatic mosaicism, with a subset of alleles having >1000 CTGs. Analyses of gene expression changes showed up-regulation of genes transcribed in microglia and endothelial cells, suggesting neuroinflammation, and downregulation of genes transcribed in neurons. Gene expression of RNAs encoding proteins detectable in cerebrospinal fluid were also found to correlate with mis-splicing, with implications for CNS biomarkers of disease severity. These findings provide a framework for future mechanistic and therapeutic studies of CNS issues in DM.
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