RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies

Guo, Shan; Nguyen, Lien; Ranum, Laura P.W.

doi:10.1016/j.conb.2021.11.001

Cited by 12 publications

(6 citation statements)

References 90 publications

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“…The information summarized here is a primer to the myriad investigations that have helped to advance our understanding of the protein context surrounding the nine polyQ disease proteins. There are numerous studies of toxic effects that are outside the scope and space dedicated to this review, but certainly provide valuable information about contributors to CAG triplet repeat expansion disorders, including repeat-association non-AUG translation and mRNA toxicity ( Zu et al, 2011 ; Cleary et al, 2018 ; Guo et al, 2022 ). These and other processes play important roles in establishing the distinct pathogenesis and clinical presentation of each polyQ disease.…”

Section: Discussionmentioning

confidence: 99%

“…This “protein context” is critical in our understanding of these diseases and paints a comprehensive picture of interactions that can be targeted as potential therapeutic entry points. (Additional, contributing factors in polyQ disorders also exist outside the realm of the disease proteins themselves, including RNA-based toxicity and unconventional translation ( Zu et al, 2011 ; Cleary et al, 2018 ; Guo et al, 2022 ); those mechanisms are outside the scope of this review).…”

Section: Introductionmentioning

confidence: 99%

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A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases

Johnson

Tsou

Prifti

et al. 2022

Front. Mol. Neurosci.

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The presence and aggregation of misfolded proteins has deleterious effects in the nervous system. Among the various diseases caused by misfolded proteins is the family of the polyglutamine (polyQ) disorders. This family comprises nine members, all stemming from the same mutation—the abnormal elongation of a polyQ repeat in nine different proteins—which causes protein misfolding and aggregation, cellular dysfunction and disease. While it is the same type of mutation that causes them, each disease is distinct: it is influenced by regions and domains that surround the polyQ repeat; by proteins with which they interact; and by posttranslational modifications they receive. Here, we overview the role of non-polyQ regions that control the pathogenicity of the expanded polyQ repeat. We begin by introducing each polyQ disease, the genes affected, and the symptoms experienced by patients. Subsequently, we provide a survey of protein-protein interactions and posttranslational modifications that regulate polyQ toxicity. We conclude by discussing shared processes and pathways that bring some of the polyQ diseases together and may serve as common therapeutic entry points for this family of incurable disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases

Johnson

Tsou

Prifti

et al. 2022

Front. Mol. Neurosci.

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“…Our method and results should enable future studies in identifying RBPs and RNA helicases that influence repeat RNA aggregation. Finally, our systematic approach of identifying sequence and structural features in repeat RNAs is not limited to the studies of RNA foci, but generalizable for studying other properties of repeat sequences, such as their impact on pre-mRNA processing (Sznajder et al, 2018), non-AUG translation (Guo et al, 2022), antisense RNA expression (Zu et al ., 2013), cytoplasmic stress granules (Fay et al ., 2017), and cell viability (Sun et al, 2020). Therefore, RepEx-PCR represents a valuable addition to the repertoire of methods enabling deeper investigations into the physiology and pathophysiology of tandem repeats and repeat expansion disorders.…”

Section: Discussionmentioning

confidence: 99%

Systematic generation and imaging of tandem repeats reveal multivalent base-pairing as a major determinant of RNA aggregation

Isiktas

Eshov

Yang

et al. 2022

Preprint

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Expansion of short tandem repeats (STRs) in the human genome underlies over fifty genetic disorders. A common pathological feature of repeat RNAs is their propensity to aggregate in cells. While these RNA aggregates have been shown to cause toxicity by sequestering RNA-binding proteins, the molecular mechanism of repeat RNA aggregation remains unclear. Here we devised a generalizable method to efficiently generate long tandem repeat DNAs de novo and applied it to systematically determine the sequence features underlying RNA aggregation. Live-cell imaging of repeat RNAs indicated that aggregation was mainly driven by multivalent RNA-RNA interactions via either canonical or noncanonical base pairs. While multiple short runs of two consecutive base pairs were sufficient, longer runs of consecutive base pairs such as those formed by a neurodegeneration-associated hexanucleotide repeat further enhanced aggregation. In summary, our study provides a unifying model for the molecular basis of repeat RNA aggregation and a generalizable approach for identifying the sequence and structural determinants of repeat RNA properties.

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“…Here, we briefly propose some possible mechanistic models of NIID at the DNA, RNA, and protein levels ( Figure 3 ). For more details, excellent review articles thoroughly discuss the various molecular mechanisms underlying pathogenesis in microsatellite diseases ( Rodriguez and Todd, 2019 ; Boivin et al, 2021 ; Depienne and Mandel, 2021 ; Malik et al, 2021 ; Guo et al, 2022 ).…”

Section: Possible Mechanisms Of Neuronal Intranuclear Inclusion Diseasementioning

confidence: 99%

Clinical and mechanism advances of neuronal intranuclear inclusion disease

Liu

et al. 2022

Front. Aging Neurosci.

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Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID (expanded GGC repeat-induced DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity) are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID.

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RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies

Cited by 12 publications

References 90 publications

A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases

A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases

Systematic generation and imaging of tandem repeats reveal multivalent base-pairing as a major determinant of RNA aggregation

Clinical and mechanism advances of neuronal intranuclear inclusion disease

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