Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima

Lin, Yunting; Xue, Jun; Deng, Jing; He, Hua; Luo, Shiyu; Chen, Jia; Li, Jia; Yu, Li; Zhao, Juan; Chen, Jing; Allen, Emily G.; Jin, Peng; Duan, Ranhui

doi:10.1016/j.nbd.2020.105013

Cited by 5 publications

(2 citation statements)

References 42 publications

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“…1 A ). The fly eye is an advantageous choice for neurodegeneration research because it is the most accessible part of the Drosophila nervous system ( 37 ). Therefore, we first used a glass multiple reporter-GALactose-regulated upstream promoter element (GMR-Gal4) driver to express uN2CpolyG in fly eyes.…”

Section: Resultsmentioning

confidence: 99%

CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model

Liufu

Zheng

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5′ untranslated region (UTR) of the NOTCH2NLC gene. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models, albeit through an unknown mechanism. Here, we established a transgenic Drosophila model expressing uN2CpolyG in multiple systems, which resulted in progressive neuronal cell loss, locomotor deficiency, and shortened lifespan. Interestingly, electron microscopy revealed mitochondrial swelling both in transgenic flies and in muscle biopsies of individuals with NIID. Immunofluorescence and immunoelectron microscopy showed colocalization of uN2CpolyG with mitochondria in cell and patient samples, while biochemical analysis revealed that uN2CpolyG interacted with a mitochondrial RNA binding protein, LRPPRC (leucine-rich pentatricopeptide repeat motif-containing protein). Furthermore, RNA sequencing (RNA-seq) analysis and functional assays showed down-regulated mitochondrial oxidative phosphorylation in uN2CpolyG-expressing flies and NIID muscle biopsies. Finally, idebenone treatment restored mitochondrial function and alleviated neurodegenerative phenotypes in transgenic flies. Overall, these results indicate that transgenic flies expressing uN2CpolyG recapitulate key features of NIID and that reversing mitochondrial dysfunction might provide a potential therapeutic approach for this disorder.

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Section: Resultsmentioning

confidence: 99%

CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model

Liufu

Zheng

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, this fly eye assay has identified several modifiers that inhibit or enhance the toxicity caused by pathogenic factors such as Tau [9][10][11], αSyn [12][13][14][15], TDP-43 [16,17] and polyglutamated HTT [18][19][20]. Moreover, drug screenings can be performed by adding compounds to fly food, and compounds that reduce disease toxicity can be identified [21,22]. Although REP has been evaluated qualitatively in most previous studies, several research groups have recently reported methods for the quantitative evaluation of REP [23,24].…”

Section: Introductionmentioning

confidence: 99%

MeDUsA: A novel system for automated axon quantification to evaluate neuroaxonal degeneration

Nitta

Kawai²,

Osaka

et al. 2021

Preprint

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Background: Drosophila is an excellent model organism for studying human neurodegenerative diseases (NDs), and the rough eye phenotype (REP) assay is a convenient experimental system for analysing the toxicity of ectopically expressed human disease genes. However, the association between REP and axonal degeneration, an early sign of ND, remains unclear. To address this question, we developed a method to evaluate axonal degeneration by quantifying the number of retinal R7 axons in Drosophila; however, it requires expertise and is time-consuming. Therefore, there is a need for an easy-to-use software that can automatically quantify the axonal degeneration. Result: We created MeDUsA (a method for the quantification of degeneration using fly axons), which is a standalone executable computer program based on Python that combines a pre-trained deep-learning masking tool with an axon terminal counting tool. This software automatically quantifies the number of axons from a confocal z-stack image series. Using this software, we have demonstrated for the first time directly that axons degenerate when the causative factors of NDs (αSyn, Tau, TDP-43, HTT) were expressed in the Drosophila eye. Furthermore, we compared axonal toxicity of the representative causative genes of NDs and their pathological alleles with REP and found no significant correlation between them. Conclusions: MeDUsA rapidly and accurately quantifies axons in Drosophila eye. By simplifying and automating time-consuming manual efforts requiring significant expertise, it enables large-scale, complex research efforts on axonal degeneration, such as screening to identify genes or drugs that mediate axonal toxicity caused by ND disease proteins.

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Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Saurat,

Minotti,

Rahman

et al. 2024

Cell Stem Cell

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Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima

Cited by 5 publications

References 42 publications

CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model

CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model

MeDUsA: A novel system for automated axon quantification to evaluate neuroaxonal degeneration

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

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