'Fly-ing' from rare to common neurodegenerative disease mechanisms

Ma, Mingfang; Moulton, Matthew J.; Lu, Shenzhao; Bellen, Hugo J.

doi:10.1016/j.tig.2022.03.018

Cited by 20 publications

(17 citation statements)

References 145 publications

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“…As human genomic data flood the present research landscape with tantalizing associations and clues to disease mechanisms, the challenging task to functionally annotate these genomic variants has become increasingly significant. Research consortia have arisen to tackle the challenges of rare and undiagnosed diseases (57,58,59), joining the efforts of individual labs in parsing the data deluge with experimentation to accelerate therapeutic target and drug discovery for more common diseases as well (37,(60)(61)(62)(63). These collective efforts have begun to bear fruit, and they are not limited to the direct relationship between genotype and phenotype alone.…”

Section: Discussionmentioning

confidence: 99%

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Nourse

Russell

Moniz

et al. 2022

Preprint

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Whole exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the TNK2 gene. Although TNK2 encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specific recessive mutations in patients resulted in aberrant or prolonged overactivity as a consequence of failed negative regulation by an E3 ubiquitin ligase, NEDD4. Interestingly, the sole Caenorhabditis elegans ortholog of TNK2, termed SID-3, is an established mediator of epigenetic gene silencing and systemic RNA interference facilitated by the SID-1 dsRNA transporter. While SID-3 had no prior association to dopamine neurotransmission in C. elegans, we hypothesized that TNK2/SID-3 represented a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Using genetic and chemical modifiers, including a TNK2 inhibitor (AIM-100) and NEDD4 activator (NAB2), in bioassays for dopamine uptake or RNAi in dopaminergic neurons of C. elegans, we determined that sid-3 mutants displayed neuroprotection from 6-hydroxydopamine (6-OHDA) exposure, as did wildtype animals treated with AIM-100 or NAB2. Additionally, NAB2 treatment of rat primary neurons correlated with a reduction of TNK2 levels and the attenuation of 6-OHDA neurotoxicity. Notably, CRISPR-modified nematodes engineered with genomic mutations in sid-3 analogous to PD patient-associated SNPs in TNK2 circumvented the resistance to RNAi characteristic of SID-3 dysfunction and furthermore exhibited enhanced susceptibility to neurodegeneration. This study describes a molecular etiology for PD whereby dysfunctional cellular dynamics, dopaminergic, and epigenetic signaling intersect to cause neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Nourse

Russell

Moniz

et al. 2022

Preprint

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“…The similarities at the molecular, cellular, and functional levels between the human and fly nervous system empower the study of gene function in flies and permit comparisons with vertebrate nervous systems ( Ugur et al, 2016 ; Ma et al, 2022 ). At the subcellular level, defects in organelles like ER, mitochondria and lysosomes are commonly observed in NDDs, which are readily detected in flies using molecular markers or transmission electron microscopy (TEM).…”

Section: Modeling Neurodegenerative Diseases Using Drosophilamentioning

confidence: 99%

“…Even for more common NDDs, such as PD and amyotrophic lateral sclerosis (ALS), where the majority of cases are sporadic, the understanding of the disease mechanism heavily relies on studies of familial cases and disease-causing genes/variants. Interestingly, some rare NDD genes are also identified as risk factors for common NDDs, suggesting that the pathogenesis of different NDDs share similar molecular mechanisms ( Ma et al, 2022 ). This is corroborated by similar pathological defects observed in various NDDs, including the presence of aberrant protein deposits and aggregates as well as deficits in lysosomal and mitochondrial functions ( Soto and Pritzkow, 2018 ; Wallings et al, 2019 ; Monzio Compagnoni et al, 2020 ; Nixon, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Fruit flies are a premier model organism for genetic studies ( Bellen et al, 2010 ). The conservation between fly and human genes and the sophisticated nervous system of flies allows for the study of NDDs in flies ( Bellen et al, 2019 ; Ma et al, 2022 ). A forward genetic screen on the Drosophila X chromosome identified 165 genes that are required for the development, function, and maintenance of the nervous system ( Yamamoto et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Sphingolipids in neurodegenerative diseases

Pan

Dutta

et al. 2023

Front. Neurosci.

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Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.

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“…Many of the latest findings have not been functionally explored in Drosophila yet ( Takai et al, 2020 ). Investigating rare diseases has also led to a better understanding of common disease etiologies, e.g., in case of neurodegenerative diseases ( Ma et al, 2022 ). This might also become the case for epilepsy caused by non-monogenic reasons.…”

Section: Drosophila Genetics and Tools To Investigate Seizur...mentioning

confidence: 99%

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Fischer

Karge²,

Weber³

et al. 2023

Front. Mol. Neurosci.

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Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

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'Fly-ing' from rare to common neurodegenerative disease mechanisms

Cited by 20 publications

References 145 publications

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Sphingolipids in neurodegenerative diseases

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

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