Neurodegeneration and locomotor dysfunction in <i>Drosophila scarlet</i> mutants

Cunningham, Patrick C.; Waldeck, Katherine; Ganetzky, Barry; Babcock, Daniel T.

doi:10.1242/jcs.216697

Cited by 16 publications

(26 citation statements)

References 44 publications

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“…Citrate synthase activity and respiratory capacity are unaffected by supplementing flies with 3-HK at a concentration known to restore it to physiological levels suggesting that mitochondrial phenotypes are independent of KMO-mediated production of 3-HK. Notably, lifespan was reduced in cn 3 flies compared to the Canton S wild-type strain, similar to a moderate decrease in lifespan previously reported in cn 1 null mutants [65]. In contrast, v 36f mutants, which lack 3-HK production but also exhibit decreased KYNA [4,5], showed a significant increase in lifespan, an observation which has also been made upon knockdown of the C. elegans orthologue tdo-2 [66].…”

Section: Plos Geneticssupporting

confidence: 86%

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

Maddison¹,

Alfonso-Núñez²,

Swaih³

et al. 2020

PLoS Genet

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The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.

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Section: Plos Geneticssupporting

confidence: 86%

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

Maddison¹,

Alfonso-Núñez²,

Swaih³

et al. 2020

PLoS Genet

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“…Run frequency and running speed are independently controlled by Drosophila nervous system (Colomb et al, 2012). Flies' walking is accompanied by global increase in activity of dopamine neurons within the brain (Aimon et al, 2019), that is in agreement with role of PPL1 neurons in movement control (Cunningham et al, 2018). Neural network responsible for generation of insect motor pulses is localized in thoracic segments (Bassler, 1983).…”

Section: Discussionsupporting

confidence: 53%

“…decreased climbing index. cn 1 also showed lower climbing index and shortened lifespan, but no loss of PPL1 neurons, which seem to be specifically susceptible to 3-HOK-induced neurodegeneration (Cunningham et al, 2018). As we investigated SLA on the horizontal plane, the negative geotaxis did not affect the flies' activity.…”

Section: Discussionmentioning

confidence: 90%

“…For the scarlet mutant with a defect in 3-HOK transport to pigment cells, age-dependent progressive loss of dopaminergic neurons belonging to Protocerebral Posterial Lateral 1 (PPL1) cluster was shown, along with increase in ROS level, shortened lifespan, and decreased climbing index. cn 1 also showed lower climbing index and shortened lifespan, but no loss of PPL1 neurons, which seem to be specifically susceptible to 3-HOK-induced neurodegeneration ( Cunningham et al, 2018 ). As we investigated SLA on the horizontal plane, the negative geotaxis did not affect the flies’ activity.…”

Section: Discussionmentioning

confidence: 99%

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3-Hydroxykynurenine in Regulation of Drosophila Behavior: The Novel Mechanisms for Cardinal Phenotype Manifestations

et al. 2020

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Dysfunctions of kynurenine pathway of tryptophan metabolism (KPTM) are associated with multiple neuropathologies in vertebrates and invertebrates. Drosophila mutants with altered content of kynurenines are model objects for studying the molecular processes of neurodegeneration and senile dementia. The mutant cardinal (cd 1) with accumulation of the redox stress inductor 3-hydroxykynurenine (3-HOK) shows age-dependent impairments of the courtship song and middle-term memory. The molecular mechanisms for 3-HOK accumulation in cd 1 are still unknown. Here, we have studied age-dependent differences in spontaneous locomotor activity (SLA) for the wild type strain CantonS (CS), cd 1 , and cinnabar (cn 1) with an excess of neuroprotective kynurenic acid (KYNA). We have also estimated the level and distribution of protein-bound 3-HOK (PB-3-HOK) in Drosophila brains (Br) and head tissues. The middle-age cd 1 show the higher running speed and lower run frequency compared to CS, for cn 1 the situation is the opposite. There is a decrease in the index of activity for 40-day-old cd 1 that seems to be an effect of the oxidative stress development. Surprisingly, PB-3-HOK level in Drosophila heads, brains, and head capsules (HC) is several times lower for cd 1 compared to CS. This complements the traditional hypothesis that cd 1 phenotype results from a mutation in phenoxazinone synthase (PHS) gene governing the brown eye pigment xanthommatin synthesis. In addition to 3-HOK dimerization, cd 1 mutation affects protein modification by 3-HOK. The accumulation of free 3-HOK in cd 1 may result from the impairment of 3-HOK conjugation with some proteins of the brain and head tissues.

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“…Our experiments in Drosophila demonstrate that accumulating α-syn causes progressive degeneration of dopaminergic neurons in an age-related manner. Interestingly, αsyn accumulation preferentially affected both PPL1 and PPM3 cluster of DA neurons that regulate motor behaviour and are specifically affected in Drosophila models of PD (Whitworth et al, 2005;Park et al, 2006;Trinh et al, 2008;Cunningham et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

Bridi

Bereczki

Smith

et al. 2020

Preprint

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Alpha-synuclein mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson's disease, Parkinson's disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying alpha-synuclein accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human alpha-synuclein leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These alpha-synuclein-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of alpha-synuclein impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that alpha-synuclein mediated synaptopathy is an initiating cause of age-related neurodegeneration.

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Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants

Cited by 16 publications

References 44 publications

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

3-Hydroxykynurenine in Regulation of Drosophila Behavior: The Novel Mechanisms for Cardinal Phenotype Manifestations

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

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