Nonapoptotic role of EGL-1 in exopher production and neuronal health in .

While traditionally studied for their proapoptotic functions in activating the caspase, research suggests BH3-only proteins also have other roles such as mitochondrial dynamics regulation. Here, we find that EGL-1, the BH3-only protein in , promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria.

Natural variation in protein kinase D modifies alcohol sensitivity in .

Differences in naïve alcohol sensitivity between individuals are a strong predictor of later life alcohol use disorders (AUD). However, the genetic bases for alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode .

Non-apoptotic role of EGL-1 in exopher production and neuronal health in .

While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein in , promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria.

Suppressing APOE4-induced mortality and cellular damage by targeting VHL.

Mortality rate increases with age and can accelerate upon extrinsic or intrinsic damage to individuals. Identifying factors and mechanisms that curb population mortality rate has wide-ranging implications. Here, we show that targeting the VHL-1 (Von Hippel-Lindau) protein suppresses mortality caused by distinct factors, including elevated reactive oxygen species, temperature, and , the genetic variant that confers high risks of neurodegeneration in Alzheimer's diseases and all-cause mortality in humans.

mScarlet and split fluorophore mScarlet resources for plasmid-based CRISPR/Cas9 knock-in in .

Fluorescent proteins allow the expression of a gene and the behavior of its protein product to be observed in living animals. The ability to create endogenous fluorescent protein tags via CRISPR genome engineering has revolutionized the authenticity of this expression, and mScarlet is currently our first-choice red fluorescent protein (RFP) for visualizing gene expression . Here, we have cloned versions of mScarlet and split fluorophore mScarlet previously optimized for into the SEC-based system of plasmids for CRISPR/Cas9 knock-in.

Learning science alongside peers with intellectual and developmental disabilities.

"Lifelong Learning with Friends" provides diversity training to college students by having them learn science alongside adults with intellectual and developmental disabilities (IDDs). Volunteers showed increased interest in IDD-focused research, social interaction, and advocacy.

Transgenerational effects of alcohol on behavioral sensitivity to alcohol in Caenorhabditis elegans.

Alcohol abuse and dependence have a substantial heritable component. Although the genome has been considered the sole vehicle of heritable phenotypes, recent studies suggest that drug or alcohol exposure may induce alterations in gene expression that are transmitted across generations. Still, the transgenerational impact of alcohol use (and abuse) remains largely unexplored in part because multigenerational studies using rodent models present challenges for time, sample size, and genetic heterogeneity.

-Induced Patterned Neurodegeneration Is Exacerbated by in .

Genetic and epidemiological studies have found that variations in the amyloid precursor protein () and the apoliopoprotein E () genes represent major modifiers of the progressive neurodegeneration in Alzheimer's disease (AD). An extra copy of or gain-of-function mutations in correlate with early onset AD. Compared to the other variants ( and ), the ε4 allele of () hastens and exacerbates early and late onset forms of AD.

Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron.

Neuronal activity often leads to alterations in gene expression and cellular architecture. The nematode Caenorhabditis elegans, owing to its compact translucent nervous system, is a powerful system in which to study conserved aspects of the development and plasticity of neuronal morphology. Here we focus on one pair of sensory neurons, termed URX, which the worm uses to sense and avoid high levels of environmental oxygen.

A quantal code for touch intensity in .

Perks and Pierce consider a new study in worms showing that touch intensity is encoded by the quantal activity of mechanoreceptors.

Activity-Dependent Regulation of the Proapoptotic BH3-Only Gene in a Living Neuron Pair in .

The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In , the BH3-only protein is expressed during development to cell-autonomously trigger most developmental cell deaths.

A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo.

Alcohol is a widely used and abused substance. A major unresolved issue in the alcohol research field is determining which of the many alcohol target proteins identified to date is responsible for shaping each specific alcohol-related behavior. The large-conductance, calcium- and voltage-activated potassium channel (BK channel) is a conserved target of ethanol.

Calnexin revealed as an ether-a-go-go chaperone by getting mutant worms up and going.

The role of ion channels in cell excitability was first revealed in a series of voltage clamp experiments by Hodgkin and Huxley in the 1950s. However, it was not until the 1970s that patch-clamp recording ushered in a revolution that allowed physiologists to witness how ion channels flicker open and closed at angstrom scale and with microsecond resolution. The unexpectedly tight seal made by the patch pipette in the whole-cell configuration later allowed molecular biologists to suck up the insides of identified cells to unveil their unique molecular contents.

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors.

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol.

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model.

The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons.

Systematic Functional Characterization of Human 21st Chromosome Orthologs in .

Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ∼200 HSA21 genes encoding proteins have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode We identified 10 HSA21 orthologs that are required for neuromuscular behaviors: (), (), (), (), (), (), (), (), (), and ().

Identifying Cellular and Molecular Mechanisms for Magnetosensation.

Diverse animals ranging from worms and insects to birds and turtles perform impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors.

Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in .

Symptoms of withdrawal from chronic alcohol use are a driving force for relapse in alcohol dependence. Thus, uncovering molecular targets to lessen their severity is key to breaking the cycle of dependence. Using the nematode , we tested whether one highly conserved ethanol target, the large-conductance, calcium-activated potassium channel (known as the BK channel or Slo1), modulates ethanol withdrawal.

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.

Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca levels in human SK-N-SH neuroblastoma cells.