CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

SUMMARYThe effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin’s polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the “polyglutamine disorders”.

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The Role of the Immune System in Triplet Repeat Expansion Diseases

Mediators of Inflammation ◽

10.1155/2015/873860 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Marta Olejniczak ◽

Martyna O. Urbanek ◽

Wlodzimierz J. Krzyzosiak

Keyword(s):

Immune System ◽

Trinucleotide Repeat ◽

Inflammatory Responses ◽

Neurological Diseases ◽

Repeat Expansion ◽

Cag Repeat ◽

Triplet Repeat ◽

Triplet Repeat Expansion ◽

Polyglutamine Disorders ◽

Intracellular Aggregates

Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

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Immunological mechanisms of chronic liver lesions under the influence of chemicals

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2019-59-9-536-537 ◽

2020 ◽

pp. 536-537

Author(s):

G. S. Agzamova ◽

M. M. Abdullaeva

Keyword(s):

The Body ◽

Chronic Liver ◽

Toxic Substances ◽

Liver Lesions ◽

Industrial Chemicals ◽

Toxic Agent ◽

Chronic Poisoning ◽

Immunological Mechanisms ◽

T System

The immunological profile of chronic liver lesions depending on the toxic agent was studied. It was revealed that chronic poisoning by industrial toxic substances causes changes in the functional state of the T-system of immunity, long-term contact with industrial chemicals leads to increased sensitization to autoantigens of the body.

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Faculty Opinions recommendation of Most meiotic CAG repeat tract-length alterations in yeast are SPO11 dependent.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005546.66106 ◽

2002 ◽

Author(s):

David Catcheside

Keyword(s):

Cag Repeat ◽

Tract Length ◽

Repeat Tract

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Autophagy Modulation as a Treatment of Amyloid Diseases

Molecules ◽

10.3390/molecules24183372 ◽

2019 ◽

Vol 24 (18) ◽

pp. 3372 ◽

Cited By ~ 21

Author(s):

Zoe Mputhia ◽

Eugene Hone ◽

Timir Tripathi ◽

Tim Sargeant ◽

Ralph Martins ◽

...

Keyword(s):

Protein Misfolding ◽

Metabolic Diseases ◽

Physiological Role ◽

Cell Loss ◽

Amyloid Proteins ◽

Tissue Degeneration ◽

Polyglutamine Disorders ◽

Amyloid Accumulation ◽

Causative Factors ◽

Amyloid Diseases

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

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Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Brain Sciences ◽

10.3390/brainsci11060710 ◽

2021 ◽

Vol 11 (6) ◽

pp. 710

Author(s):

Jannis Achenbach ◽

Simon Faissner ◽

Carsten Saft

Keyword(s):

Hiv Infection ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Diagnostic Delay ◽

Depression Scale ◽

Cag Repeat ◽

Psychiatric Disease ◽

Disease Manifestation ◽

Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

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The CAG Repeat Within the Androgen Receptor Gene and Benign Prostatic Hyperplasia

The Journal of Urology ◽

10.1097/00005392-199907000-00090 ◽

1999 ◽

Vol 162 (1) ◽

pp. 269-270

Author(s):

E. Giovannucci ◽

E.A. Platz ◽

M.J. Stampfer ◽

A. Chan ◽

K. Krithivas ◽

...

Keyword(s):

Androgen Receptor ◽

Benign Prostatic Hyperplasia ◽

Receptor Gene ◽

Androgen Receptor Gene ◽

Prostatic Hyperplasia ◽

Cag Repeat

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The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

Journal of Huntington s Disease ◽

10.3233/jhd-200429 ◽

2021 ◽

Vol 10 (1) ◽

pp. 7-33

Author(s):

Darren G. Monckton

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Human Genetics ◽

Age At Onset ◽

Cag Repeat ◽

Model Systems ◽

Causative Mutation ◽

Inverse Association ◽

Independent Manner ◽

Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

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The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Diagnostics ◽

10.3390/diagnostics11061051 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1051

Author(s):

Valentina Bessi ◽

Salvatore Mazzeo ◽

Silvia Bagnoli ◽

Giulia Giacomucci ◽

Assunta Ingannato ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Spatial Ability ◽

Cognitive Status ◽

Cag Repeat ◽

Cag Repeats ◽

Subjective Cognitive Decline ◽

Visual Spatial ◽

Premorbid Intelligence

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

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Use of single guided Cas9 nickase to facilitate precise and efficient genome editing in human iPSCs

Scientific Reports ◽

10.1038/s41598-021-89312-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pan P. Li ◽

Russell L. Margolis

Keyword(s):

Genome Editing ◽

Disease Modeling ◽

Neurodegenerative Disorder ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

End Joining ◽

Human Ipscs ◽

Non Homologous End Joining ◽

Transient Overexpression ◽

Donor Template

AbstractCas9 nucleases permit rapid and efficient generation of gene-edited cell lines. However, in typical protocols, mutations are intentionally introduced into the donor template to avoid the cleavage of donor template or re-cleavage of the successfully edited allele, compromising the fidelity of the isogenic lines generated. In addition, the double-stranded breaks (DSBs) used for editing can introduce undesirable “on-target” indels within the second allele of successfully modified cells via non-homologous end joining (NHEJ). To address these problems, we present an optimized protocol for precise genome editing in human iPSCs that employs (1) single guided Cas9 nickase to generate single-stranded breaks (SSBs), (2) transient overexpression of BCL-XL to enhance survival post electroporation, and (3) the PiggyBac transposon system for seamless removal of dual selection markers. We have used this method to modify the length of the CAG repeat contained in exon 7 of PPP2R2B. When longer than 43 triplets, this repeat causes the neurodegenerative disorder spinocerebellar ataxia type 12 (SCA12); our goal was to seamlessly introduce the SCA12 mutation into a human control iPSC line. With our protocol, ~ 15% of iPSC clones selected had the desired gene editing without “on target” indels or off-target changes, and without the deliberate introduction of mutations via the donor template. This method will allow for the precise and efficient editing of human iPSCs for disease modeling and other purposes.

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