Dynamics of escaping flight initiations of Drosophila melanogaster

Zabalax, F.A.; Card, Gwyneth M; Fontaine, E.; Murray, Richard M.; Dickinson, Michael H.

doi:10.1109/biorob.2008.4762921

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…Inhibition of specific TH-positive DA neurons has been found to compromise flight, including impaired wing coordination and kinematics ( Sadaf et al, 2015 ). Initiating voluntary flight (take-off) consists of an initial phase of wing elevation, followed by a second phase of simultaneous left- and right-wing depression and leg extension ( Zabalax et al, 2008 ). Using a high-speed camera (2000 fps), we quantified the time that elapsed between the initiation of wing elevation (t = 0) and final take-off from a water surface ( Figure 2A and Videos 1 – 2 ).…”

Section: Resultsmentioning

confidence: 99%

Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

Aguilar

Cheng

Font

et al. 2021

eLife

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Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

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Section: Resultsmentioning

confidence: 99%

Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

Aguilar

Cheng

Font

et al. 2021

eLife

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show abstract

“…Inhibition of specific TH-positive DA neurons has been found to compromise flight, including impaired wing coordination and kinematics (Sadaf et al, 2015). Initiating voluntary flight (take-off) consists of an initial phase of wing elevation, followed by a second phase of simultaneous left- and right-wing depression and leg extension (Zabalax et al, 2008). Using a high-speed camera (2,000 fps), we quantified the time that elapsed between the initiation of wing elevation (t = 0) and final take-off from a water surface ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Psychomotor Impairments and Therapeutic Implications Revealed by a Mutation Associated with Infantile Parkinsonism-Dystonia

Aguilar

Cheng

Font

et al. 2021

Preprint

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Parkinson's disease (PD) is a neurodegenerative disorder affecting over 6.1 million people worldwide. Studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the mechanisms underlying PD. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a type of infantile parkinsonism-dystonia that shares clinical features with PD. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. This R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. The disruption of this IC network supported a channel-like intermediate of hDAT and compromised hDAT function. Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, DA dysfunction in isolated brains and abnormal motor behaviors monitored at high-speed time resolution. These behaviors are linked with altered dopaminergic signaling, loss of DA neurons and decreased DA availability.

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Directionality control and flight stability of takeoff

Zabala

2009

2009 IEEE International Conference on Robotics and Automation

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Dynamics of escaping flight initiations of Drosophila melanogaster

Cited by 3 publications

References 27 publications

Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

Psychomotor Impairments and Therapeutic Implications Revealed by a Mutation Associated with Infantile Parkinsonism-Dystonia

Directionality control and flight stability of takeoff

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