Modeling Huntington disease in
            <i>Drosophila</i>

Krench, Megan Attardo; Littleton, J Troy

doi:10.4161/fly.26279

Cited by 31 publications

(24 citation statements)

References 37 publications

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“…Polyglutamine (PolyQ) expansion disorders were some of the first diseases to be studied using this approach, by overexpressing PolyQ proteins associated with spinocerebellar ataxia type 3 (Warrick et al 1998) or Huntington's disease (Jackson et al 1998), and Drosophila remains a useful model for examining PolyQ protein dynamics and neurodegeneration (Krench and Littleton 2013). Other notable neurodegenerative diseases modeled in flies include Parkinson's disease, Alzheimer's disease, and prion diseases (Bier 2005;Rincon-Limas et al 2012).…”

Section: Resultsmentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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Section: Resultsmentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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“…HTT moves bi-directionally within larval axons in vivo (Fig. S4a) [7,36,75], although Drosophila lacks a true homologue of HAP1. Reduction of endogenous Drosophila htt (using htt-RNAi or the knock-out mutant) disrupted the motility of nonpathogenic human HTT indicating that the motility of HTT15Q-mRFP is dependent on endogenous Drosophila htt (Fig.…”

Section: The Putative Moving Htt-rab4 Vesicle Contains Synaptic Protementioning

confidence: 99%

“…Indeed, axonal transport defects have been observed in HD prior to behavioral defects and neuronal cell death in flies [24], mice [71], and humans [64], indicating that perturbations in trafficking can occur early in the development of HD [24,27]. Further, HTT moves bidirectionally within axons [7] and reduction of Drosophila HTT (htt) causes axonal accumulations [24,36,75,76], similar to what has been observed with loss of motor protein function [23]. Loss of HTT in mammalian neurons also disrupts the transport of brain-derived neurotrophic factor (BDNF), which was partially rescued by the expression of htt, indicating a conserved role for HTT during axonal transport.…”

Section: Introductionmentioning

confidence: 99%

Excess Rab4 rescues synaptic and behavioral dysfunction caused by defective HTT-Rab4 axonal transport in Huntington’s disease

White

Krzystek

Hoffmar-Glennon

et al. 2020

acta neuropathol commun

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Huntington's disease (HD) is characterized by protein inclusions and loss of striatal neurons which result from expanded CAG repeats in the poly-glutamine (polyQ) region of the huntingtin (HTT) gene. Both polyQ expansion and loss of HTT have been shown to cause axonal transport defects. While studies show that HTT is important for vesicular transport within axons, the cargo that HTT transports to/from synapses remain elusive. Here, we show that HTT is present with a class of Rab4-containing vesicles within axons in vivo. Reduction of HTT perturbs the bidirectional motility of Rab4, causing axonal and synaptic accumulations. In-vivo dual-color imaging reveal that HTT and Rab4 move together on a unique putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors for its bi-directional movement within axons, as well as the accessory protein HIP1 (HTT-interacting protein 1). Pathogenic HTT disrupts the motility of HTT-Rab4 and results in larval locomotion defects, aberrant synaptic morphology, and decreased lifespan, which are rescued by excess Rab4. Consistent with these observations, Rab4 motility is perturbed in iNeurons derived from human Huntington's Disease (HD) patients, likely due to disrupted associations between the polyQ-HTT-Rab4 vesicle complex, accessory proteins, and molecular motors. Together, our observations suggest the existence of a putative moving HTT-Rab4 vesicle, and that the axonal motility of this vesicle is disrupted in HD causing synaptic and behavioral dysfunction. These data highlight Rab4 as a potential novel therapeutic target that could be explored for early intervention prior to neuronal loss and behavioral defects observed in HD.

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“…These pathways include transcription regulation [9], axonal transport [10], endocytosis [11], mitochondrial metabolism [12] and protein degradation [13]. It remains a major challenge to establish when each of these defects occur during HD pathogenesis and hence discern primary cellular defects that initiate the disease process from secondary effects that merely reflect a degenerating cellular state.…”

Section: Huntington's Disease and Other Polyglutamine Expansion Diseasesmentioning

confidence: 99%

Cellular Stress Responses in Protein Misfolding Diseases

Duennwald

2015

Future Sci. OA

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Many human diseases, particularly neurodegenerative diseases, are associated with protein misfolding. Cellular protein quality control includes all processes that ensure proper protein folding and thus prevent the toxic consequences of protein misfolding. The heat shock response (HSR) and the unfolded protein response (UPR) are major stress response pathways within protein quality control that antagonize protein misfolding in the cytosol and the endoplasmic reticulum, respectively. Huntington's disease is an inherited neurodegenerative disease caused by the misfolding of an abnormally expanded polyglutamine (polyQ) region in the protein huntingtin (Htt), polyQHtt. Using Huntington's disease as a paradigm, I review here the central role of both the HSR and the UPR in defining the toxicity associated with polyQHtt in Huntington's disease. These findings may begin to unravel a previously unappreciated cooperation between different stress response pathways in cells expressing misfolded proteins and consequently in neurodegenerative diseases.

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Modeling Huntington disease in Drosophila

Cited by 31 publications

References 37 publications

Transmission, Development, and Plasticity of Synapses

Transmission, Development, and Plasticity of Synapses

Excess Rab4 rescues synaptic and behavioral dysfunction caused by defective HTT-Rab4 axonal transport in Huntington’s disease

Cellular Stress Responses in Protein Misfolding Diseases

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