Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools

Karwacka, Marianna; Olejniczak, Marta

doi:10.3390/cells11030517

Cited by 10 publications

(14 citation statements)

References 179 publications

(289 reference statements)

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“…Table 2. Normal and pathogenic CAG repeat ranges reported in 2013 [116], 2017 [85], 2020 [115], 2021 [117] and 2022 [125] in the context of polyQ-related disorders. The intermediate/pre-mutation repeat ranges were not considered.…”

Section: Polyq Expansions and Neurodegenerationmentioning

confidence: 98%

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

Moldovean-Cioroianu

2024

IJMS

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Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure–function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure–function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins’ dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders.

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Section: Polyq Expansions and Neurodegenerationmentioning

confidence: 98%

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

Moldovean-Cioroianu

2024

IJMS

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“…36 Table 1. Polyglutamine (polyQ) repeat expansion diseases 1,22,25,[36][37][38][39][40][41][42][43][44][45]…”

Section: Polyq Diseases Definition and Common Features Of Polyq Disea...mentioning

confidence: 99%

“…A variety of cellular models include (i) fibroblasts extracted from patients by a skin biopsy 188,189 ; (ii) embryonic stem cells, which contain disease-associated genetic patterns and can be further differentiated into any cell in the human body 190 ; (iii) induced pluripotent stem cells comprising patient-specific genetic information, dividing unlimitedly and able to be differentiated into any disease-related cell populations, including neurons 191,192 ; (iv) human embryonic kidney 293 (HEK 293T) cells having the advantage of simple transfection and high-level transgene expression 193 ; and (v) yeast cell models, inexpensive and appropriate for large-scale genetic and pharmacological screening. 45 Further, animal models exhibiting more advanced phenotypes and typical behaviors are an essential requisite for polyQ disease modeling. Simple model organisms include the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio.…”

Section: Landscape Of Polyq Disease Researchmentioning

confidence: 99%

“…They helped verify pathogenic features of polyQ diseases such as the aggregate formation, the mutant proteins toxicity, the neurotransmission deficiencies and the progressive neuronal degeneration. 45 Rodent models have been successfully used in studying behavioral phenotypes of Huntington's disease. 194 Recently, large mammalian models of Huntington's disease and SCA3 in monkeys, marmosets, minipigs, pigs, and sheep have been generated by using genome-editing technology.…”

Section: Landscape Of Polyq Disease Researchmentioning

confidence: 99%

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Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Tenchov,

Sasso,

Zhou

2024

Preprint

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.

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“…Neurogenomics has paved the way for gene editing technologies like CRISPR-Cas 9 . These tools offer the potential to correct disease-causing genetic mutations directly at the DNA level 35 .…”

Section: Precision Medicine and Therapies In Neurodegenerative Diseasesmentioning

confidence: 99%

Neurogenomics contribution to neurodegenerative Diseases

Adeleye,

Olorunlowu,

Yusuf

et al. 2024

Nep J Neurosci

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Introduction: Neurodegenerative diseases are a group of complex disorders that progressively impair the structure and function of the nervous system, resulting in debilitating symptoms and reduced quality of life for affected individuals. Over the past few decades, advances in the field of genomics have revolutionized our understanding of the underlying molecular mechanisms driving these disorders. Neurogenomics, the intersection of neuroscience and genomics, has emerged as a crucial discipline in unraveling the genetic and molecular underpinnings of neurodegenerative diseases. Neurogenomics focuses on deciphering the genetic variations that contribute to the susceptibility and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Advances in DNA sequencing technologies have enabled researchers to identify specific genetic mutations and variations that are associated with increased disease risk. By studying the genetic mutations involved in neurodegenerative diseases, neurogenomics has provided valuable insights into the underlying disease mechanisms. These insights have led to a deeper understanding of protein aggregation, mitochondrial dysfunction, inflammation, and other cellular processes implicated in disease progression. By harnessing the power of neurogenomics through further studies, researchers and clinicians are moving closer to the goal of effectively preventing, diagnosing, and treating neurodegenerative diseases, thus offering hope to millions of individuals affected by these challenging conditions. Conclusion: Neurogenomics has emerged as a pivotal field in unraveling the complex interplay between genetics and neurobiology in neurodegenerative diseases. By dissecting the genetic architecture, elucidating molecular mechanisms, and paving the way for targeted therapies, neurogenomics offers new avenues for understanding, diagnosing, and ultimately treating these disorders.

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Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools

Cited by 10 publications

References 179 publications

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Neurogenomics contribution to neurodegenerative Diseases

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