Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Lee, Won-Seok; Al‐Ramahi, Ismael; Jeong, Hyun-Hwan; Jang, Youjin; Lin, Tao; Adamski, Carolyn J.; Lavery, Laura A.; Rath, Smruti; Richman, Ronald; Bondar, Vitaliy V.; Alcala, Elizabeth; Revelli, Jean‐Pierre; Orr, Harry T.; Liu, Zhandong; Botas, Juan; Zoghbi, Huda Y.

doi:10.1172/jci156616

Cited by 8 publications

(6 citation statements)

References 56 publications

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“…Further experiments, both in Drosophila and in human cells, showed that TG2 reduction ameliorates the defects in both PD and HD ( Karpuj et al, 2002 ; McConoughey et al, 2010 ; Min et al, 2015 ). Similarly, a role for TG5 in enhancing the toxicity of mutant ATXN1 was shown in Drosophila models and in cells from SCA1-patients where TG5 was shown to colocalize with Ataxin1 ( Lee et al, 2022b ) further supporting a functional role for this enzymes in the disease. Genetic screen and chemical inhibitors revealed the RAS-MAPK–MSK1 as an important axis in the control of Ataxin1 aggregate formation ( Park et al, 2013 ).…”

Section: Neurodegenerative Proteinopathies or (Pps)mentioning

confidence: 75%

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: 75%

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

et al. 2023

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“…7d , thick blue arrow and blue arrowhead). The high molecular weight bands could be Atxn1 molecules cross-linked by transglutaminase 5 43 that escaped from protein degradation. Immunostaining of Atxn1 and ISG15 or Ub and ISG15 revealed they co-localized in the nucleus (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage

Homma,

Yoshioka,

Fujita

et al. 2024

Commun Biol

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Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients.

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“…Lastly, we compare PARMESAN’s gene-gene relationship predictions to two in vitro disease gene modifier screens. One for genes whose knockdown decreases ATXN1 levels 18 , and one for druggable genes whose knockdown increases or decreases endogenous and over-expressed TAU protein in a human cell line. PARMESAN’s correct predictions outnumber the incorrect ones, and filtering the predictions by score significantly favors the correct predictions in the ATXN1 screen, but not the TAU screen (p=0.0003 and 0.5568, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…Lastly, we compare PARMESAN gene-gene relationship predictions to screens for modifiers of ATXN1 and TAU . The ATXN1 screen includes 93 genes whose downregulation leads to reduced ATXN1 levels (positive regulators identified in Lee et al, which had hits in non- Drosophila models) 18 . The TAU screen includes 97 genes whose knockdown decreased (92, positive regulators) or increased (5, negative regulators) endogenous and over-expressed TAU protein in a human cell line.…”

Section: Methodsmentioning

confidence: 99%

Literature-based predictions of treatments for genetic disease pathology

Deisseroth

Lee

Kim

et al. 2022

Preprint

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Identifying genetic modifiers of disease-causing genes can guide drug discovery for treatment of genetic disorders, but selecting promising drugs to test requires extensive and up-to-date knowledge of drug-gene and gene-gene relationships. To address this challenge, we present PARsing ModifiErS via Abstract aNnotations (PARMESAN), a computational tool that searches PubMed for information on these relationships, and assembles them into one knowledgebase. PARMESAN then hypothesizes on undiscovered drug-gene relationships, assigning an evidence-based score to each hypothesis. We compare PARMESAN's drug-gene hypotheses to all of the drug-gene relationships displayed by DrugBank, and see a strong correlation between the prediction score and the predictive accuracy such that predictions scoring above 10 are 11 times more likely to be correct than incorrect. This publicly available tool provides an automated way to prioritize drug screens to target the most-promising drugs to test, thereby saving time and resources in the development of therapeutics for genetic disorders.

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Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Cited by 8 publications

References 56 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

Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage

Literature-based predictions of treatments for genetic disease pathology

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