Age-dependent degeneration of an identified adult leg motor neuron in a <i>Drosophila</i> SOD1 model of ALS

Agudelo, Anthony; Amand, Victoria St.; Grissom, Lindsey; Lafond, Danielle; Achilli, Toni; Şahin, Aslı; Reenan, Robert A.; Stilwell, Geoff

doi:10.1242/bio.049692

Cited by 6 publications

(6 citation statements)

References 82 publications

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“…Studies in Drosophila and in mice demonstrated that expression of human SOD1 in motor neurons reduced ROS activity, leading to longevity ( Parkes et al, 1998 ; Missirlis et al, 2001 ). Further studies in flies demonstrated that the enzymatic activity of human SOD1 is not required for its toxicity: In fact, homozygous inactive SOD1 mutants (G85R, H48R, and H71Y) expression in dSOD1 null flies results in neurodegeneration, motor defects, and shortened life span, suggesting that these phenotypes are associated to SOD1-mutations rather than SOD1 activity ( Şahin et al, 2017 ; Agudelo et al, 2020 ). Expression of mutants SOD-1 results in deposition of protein aggregates visible in neurons, glia and in skeletal muscles in both mice-of ALS and cells from ALS patients ( Dirren et al, 2015 ).…”

Section: Neurodegenerative Proteinopathies or (Pps)mentioning

confidence: 99%

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Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

et al. 2023

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Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington’s disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer’s disease (APP, Tau) Parkinson’s disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.

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Section: Neurodegenerative Proteinopathies or (Pps)mentioning

confidence: 99%

“…SOD1 is involved in protein misfolding, and it is necessary for neuronal health ( Şahin et al, 2017 ; Agudelo et al, 2020 )…”

Section: Introductionmentioning

confidence: 99%

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

et al. 2023

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“…A number of fly models have been generated looking at SOD1 function in disease development. Both gain and loss of function models have been generated, as it is still a matter of debate whether ALS caused by SOD1 mutations is due to a gain or loss of function of the protein ( Mockett et al, 2003 ; Şahin et al, 2017 ; Agudelo et al, 2020 ).…”

Section: Fly Models Of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis And Their Role In Mitochondrial Dysfunctionmentioning

confidence: 99%

Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models

2021

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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by declining motor and cognitive functions. Even though these diseases present with distinct sets of symptoms, FTD and ALS are two extremes of the same disease spectrum, as they show considerable overlap in genetic, clinical and neuropathological features. Among these overlapping features, mitochondrial dysfunction is associated with both FTD and ALS. Recent studies have shown that cells derived from patients’ induced pluripotent stem cells (iPSC)s display mitochondrial abnormalities, and similar abnormalities have been observed in a number of animal disease models. Drosophila models have been widely used to study FTD and ALS because of their rapid generation time and extensive set of genetic tools. A wide array of fly models have been developed to elucidate the molecular mechanisms of toxicity for mutations associated with FTD/ALS. Fly models have been often instrumental in understanding the role of disease associated mutations in mitochondria biology. In this review, we discuss how mutations associated with FTD/ALS disrupt mitochondrial function, and we review how the use of Drosophila models has been pivotal to our current knowledge in this field.

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“…Drosophila Sod loss-of-function mutants exhibit elevated levels of reactive oxygen species (ROS) combined with a drastically shortened adult lifespan (median ~11 d. vs 50 d. for wild-type flies at 25 °C, Phillips et al, 1989) and reduced locomotor ability in larvae (Şahin et al, 2017) and adults (Ruan & Wu, 2008). Coupled with these longevity and behavioral phenotypes, several neuromuscular deficits have recently been identified in Sod loss-of-function mutants including deranged nerve and synapse morphology in larvae (Milton et al, 2011) and adults (Agudelo et al, 2020; Şahin et al, 2017), as well as disrupted neurotransmission along the giant-fiber (GF) jump-and-flight escape circuit (Iyengar et al, 2020; Iyengar, 2016; Ruan, 2008). Given the striking phenotypes, a question that arises is: To what extent the straightforward assumption holds that aspects of the Sod phenotypes can be recapitulated by pharmacologically induced oxidative stress?…”

Section: Descriptionmentioning

confidence: 99%

Differential effects on neuromuscular physiology betweenSodloss-of-function mutation and paraquat-induced oxidative stress inDrosophila

Ueda

Iyengar

2021

Preprint

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Oxidative stress is thought to be a major contributor to aging processes. Here, we report differential effects on neurotransmission caused by loss-of-function mutations of Superoxide dismutase (Sod) and by paraquat (PQ) feeding in Drosophila. We demonstrated alterations in Sod mutants; the larval neuromuscular junction displayed supernumerary discharges and the adult giant-fiber escape pathway showed increased latency and poor response to repetitive high-frequency stimulation. Even though the concentrations used led to motor coordination defects and lethality, PQ feeding failed to reproduce such performance deficits in these larval and adult preparations, indicating mechanistic distinctions between genetic and pharmacological manipulation of oxidative stress.

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Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS

Cited by 6 publications

References 82 publications

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models

Differential effects on neuromuscular physiology betweenSodloss-of-function mutation and paraquat-induced oxidative stress inDrosophila

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