Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures

Monteiro, Olivia; Chen, Changwei; Bingham, Ryan P.; Argyrou, Argyrides; Buxton, Rachel; Jönsson, Christina Pancevac; Jones, Emma; Bridges, Angela; Gatfield, Kelly M; Krauß, Sybille; Lambert, Jeremy J.; Langston, Rosamund F.; Schweiger, Susann; Uings, Iain

doi:10.1016/j.neulet.2018.02.061

Cited by 9 publications

(10 citation statements)

References 26 publications

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“…In another study, a peptide that is able to disrupt the interaction between MID1 and alpha4 was used disrupt the MID1-complex within cells. As expected, this results in decreased HTT protein expression in cultures of neurones derived from HD mice (Monteiro et al, 2018). Together, these data validate that the MID1 complex is a valuable drug target and pave the way for the further development and refinement of small molecule inhibitors of this interaction as potential therapies for HD.…”

Section: Targeting Mid1supporting

confidence: 78%

The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

et al. 2021

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Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

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Section: Targeting Mid1supporting

confidence: 78%

The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

et al. 2021

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“…This leads to the activation of S6 K and the facilitation of mHTT mRNA translation. MID1 also associates with the CAG-repeat of m HTT in a length-dependent manner, increasing the production of mHTT even more [ 265 ].…”

Section: Post-translational Modifications In Selected Cellular Evementioning

confidence: 99%

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay

Kiss

Virág

et al. 2020

IJMS

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.

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“…The action is the way the modifier gene is being manipulated, and the predicate is the effect that manipulating the modifier has on the target gene. As an example, Monteiro et al published an article titled, “Pharmacological disruption of the MID1/ α 4 interaction reduces mutant Huntingtin levels in primary neuronal cultures” 15 . The modifier and target are MID1 and Huntingtin, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…As it is presented here, PARMESAN uses all PubMed abstracts accessed via PubMed’s FTP site on September 4, 2022. We will present PARMESAN’s extraction process in the context of extracting the relationship described in Monteiro et al, where disrupting MID1 activity decreases Huntingtin levels 15 . This extraction is also displayed diagrammatically in Figure 1.…”

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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Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures

Cited by 9 publications

References 26 publications

The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Literature-based predictions of treatments for genetic disease pathology

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