Synaptic defects in a drosophila model of muscular dystrophy.

Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases.

Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila.

Maintaining synaptic communication is required to preserve nervous system function as an organism ages. While much work has been accomplished to understand synapse formation and development, we understand relatively little regarding maintaining synaptic integrity throughout aging. To better understand the mechanisms responsible for maintaining synaptic structure and function, we performed an unbiased forward genetic screen to identify genes required for synapse maintenance of adult Drosophila neuromuscular junctions.

Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

The hallmark of Parkinson's disease (PD) is the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. We previously completed a screen identifying genes associated with the progressive degeneration of DA neurons.

Behavioral Nudges as Patient Decision Support for Medication Adherence: The ENCOURAGE Randomized Controlled Trial.

Background: Medication adherence is generally low and challenging to address because patient actions control healthcare delivery outside of medical environments. Behavioral nudging changes clinician behavior, but nudging patient decision-making requires further testing. This trial evaluated whether behavioral nudges can increase statin adherence, measured as the proportion of days covered (PDC).

Characterizing dopaminergic neuron vulnerability using genome-wide analysis.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. To identify genes that are associated with DA neuron loss, we screened through 201 wild-caught populations of Drosophila melanogaster as part of the Drosophila Genetic Reference Panel.

sustains trans-synaptic BMP signaling required for synaptic maintenance with age.

Maintaining synaptic structure and function over time is vital for overall nervous system function and survival. The processes that underly synaptic development are well understood. However, the mechanisms responsible for sustaining synapses throughout the lifespan of an organism are poorly understood.

Visualizing Synaptic Degeneration in Adult Drosophila in Association with Neurodegeneration.

Drosophila serves as a useful model for assessing synaptic structure and function associated with neurodegenerative diseases. While much work has focused on neuromuscular junctions (NMJs) in Drosophila larvae, assessing synaptic integrity in adult Drosophila has received much less attention. Here we provide a straightforward method for dissection of the dorsal longitudinal muscles (DLMs), which are required for flight ability.

Neurodegeneration and locomotor dysfunction in mutants.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, resulting in progressive locomotor dysfunction. Identification of genes required for the maintenance of these neurons should help to identify potential therapeutic targets. However, little is known regarding the factors that render dopaminergic neurons selectively vulnerable to PD.

Drosophila caspase activity is required independently of apoptosis to produce active TNF/Eiger during nociceptive sensitization.

Tumor necrosis factor (TNF) signaling is required for inflammatory nociceptive (pain) sensitization in Drosophila and vertebrates. Nociceptive sensitization in Drosophila larvae following UV-induced tissue damage is accompanied by epidermal apoptosis and requires epidermal-derived TNF/Eiger and the initiator caspase, Dronc. Major gaps remain regarding TNF function in sensitization, including the relationship between apoptosis/tissue damage and TNF production, the downstream signaling in this context, and the target genes that modulate nociceptive behaviors.

Non-cell autonomous cell death caused by transmission of Huntingtin aggregates in Drosophila.

Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined.

Tachykinin acts upstream of autocrine Hedgehog signaling during nociceptive sensitization in Drosophila.

Pain signaling in vertebrates is modulated by neuropeptides like Substance P (SP). To determine whether such modulation is conserved and potentially uncover novel interactions between nociceptive signaling pathways we examined SP/Tachykinin signaling in a Drosophila model of tissue damage-induced nociceptive hypersensitivity. Tissue-specific knockdowns and genetic mutant analyses revealed that both Tachykinin and Tachykinin-like receptor (DTKR99D) are required for damage-induced thermal nociceptive sensitization.

Transcellular spreading of huntingtin aggregates in the Drosophila brain.

A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease.

A neuroprotective function of NSF1 sustains autophagy and lysosomal trafficking in Drosophila.

A common feature of many neurodegenerative diseases is the accumulation of toxic proteins that disrupt vital cellular functions. Degradative pathways such as autophagy play an important protective role in breaking down misfolded and long-lived proteins. Neurons are particularly vulnerable to defects in these pathways, but many of the details regarding the link between autophagy and neurodegeneration remain unclear.

An improved method for accurate and rapid measurement of flight performance in Drosophila.

Drosophila has proven to be a useful model system for analysis of behavior, including flight. The initial flight tester involved dropping flies into an oil-coated graduated cylinder; landing height provided a measure of flight performance by assessing how far flies will fall before producing enough thrust to make contact with the wall of the cylinder. Here we describe an updated version of the flight tester with four major improvements.

Hedgehog signaling regulates nociceptive sensitization.

Background: Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets.

Two sides of the same coin no longer: genetic separation of nociceptive sensitization responses.

Nociceptive sensitization is a conserved form of neuronal plasticity that serves an important survival function, as it fosters behavior that protects damaged tissue during healing. This sensitization may involve a lowering of the nociceptive threshold (allodynia) or an increased response to normally noxious stimuli (hyperalgesia). Although nociceptive sensitization has been intensively studied in vertebrate models, an open question in the field is the extent to which allodynia and hyperalgesia, which almost always occur in tandem, are truly separate events at the mechanistic level.

Cytokine signaling mediates UV-induced nociceptive sensitization in Drosophila larvae.

Background: Heightened nociceptive (pain) sensitivity is an adaptive response to tissue damage and serves to protect the site of injury. Multiple mediators of nociceptive sensitization have been identified in vertebrates, but the complexity of the vertebrate nervous system and tissue-repair responses has hindered identification of the precise roles of these factors.

Results: Here we establish a new model of nociceptive sensitization in Drosophila larvae, in which UV-induced tissue damage alters an aversive withdrawal behavior.

Active cop, passive cop: developmental stage-specific modes of wound-induced blood cell recruitment in Drosophila.

In the past few years a number of fly labs have studied wounded Drosophila embryos,(1-3) larvae(4-6) and adults7 in an effort to uncover the molecular/genetic basis of wound healing responses. The early studies in this growing field focused on the signature event of wound healing--the closure of the epidermal gap through cell migration. These studies showed that there is a conserved dichotomy between embryonic and postembryonic repair processes in flies and vertebrates: embryonic wounds heal through contraction of a supracellular actin pursestring assembled at the wound margin and postembryonic wounds heal through extension of cell processes and migration across the wound gap.

Circulating blood cells function as a surveillance system for damaged tissue in Drosophila larvae.

Insects have an open circulatory system in which the heart pumps blood (hemolymph) into the body cavity, where it directly bathes the internal organs and epidermis. The blood contains free and tissue-bound immune cells that function in the inflammatory response. Here, we use live imaging of transgenic Drosophila larvae with fluorescently labeled blood cells (hemocytes) to investigate the circulatory dynamics of larval blood cells and their response to tissue injury.