The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

Mapping Intimacies ◽

10.14293/s2199-1006.1.sor-.ppmg8mr.v1 ◽

2020 ◽

Author(s):

Alana Alvarez-Amado

Keyword(s):

Protein Interactions ◽

Trinucleotide Repeat ◽

Fragile X ◽

Neurological Diseases ◽

Neuronal Loss ◽

Threshold Effect ◽

Cag Repeats ◽

Huntingtin Protein ◽

Neuronal Processes ◽

Fmr1 Mrna

Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1 mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS.

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The quest towards understanding the molecular pathogenesis of triplet repeat disorders: Huntingtons Disease and Fragile X-Associated Tremor and Ataxia Syndrome

10.14293/s2199-1006.1.sor-.ppdknva.v1 ◽

2020 ◽

Author(s):

Alana Amado ◽

Alana Amado

Keyword(s):

Protein Interactions ◽

Trinucleotide Repeat ◽

Fragile X ◽

Neurological Diseases ◽

Neuronal Loss ◽

Threshold Effect ◽

Cag Repeats ◽

Huntingtin Protein ◽

Cgg Repeats ◽

Neuronal Processes

Trinucleotide repeat disorders encompass a group of neurological diseases driven by unstable repeat expansions. Huntingtons disease (HD) is characterized by chorea and brain atrophy. The normal huntingtin protein contains 6-34 CAG repeats; however, upon a threshold effect of >36 repeats, the huntingtin protein acquires toxic mechanisms that are harmful to the cell. Fragile X-Associated Tremor and Ataxia (FXTAS) is characterized by tremor, ataxia and neuronal loss. The normal FMR1 gene contains 5-45 CGG repeats; however, upon a premutation CGG expansion of 55-200, FXTAS arises. A pathological hallmark of these disorders includes aggregate formation within the brain; suggestive of impaired protein and mRNA function. Furthermore, important molecules have been found to be sequestered into these aggregates withdrawing them from their normal roles. In this review, the ways mutant huntingtin and FMR1mRNA aggregates induce intracellular dysfunction in HD and FXTAS is analyzed, specifically in the context of impaired neuronal processes and protein-protein interactions. Analysis revealed that huntingtin and FMR1 mRNA are involved in the regulation of multiple cellular pathways; and whose impaired function results in a detrimental domino-effect that is destructive to the cell. The understanding of these molecular processes hopes to identify potential targets towards the treatment of HD and FXTAS

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Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

10.26434/chemrxiv.12052869.v1 ◽

2020 ◽

Author(s):

James Frederich ◽

Ananya Sengupta ◽

Josue Liriano ◽

Ewa A. Bienkiewicz ◽

Brian G. Miller

Keyword(s):

Protein Interactions ◽

Neurological Diseases ◽

Adapter Proteins ◽

Protein Protein Interactions ◽

Specific Expression ◽

Individual Client ◽

Isoform Specificity ◽

Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

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Faculty Opinions recommendation of Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome.

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

10.3410/f.718290968.793493498 ◽

2014 ◽

Author(s):

Tony Weil

Keyword(s):

Fragile X Syndrome ◽

Trinucleotide Repeat ◽

Fragile X ◽

Epigenetic Silencing

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Patients With Extreme Early Onset Juvenile Huntington Disease Can Have Delays in Diagnosis: A Case Report and Literature Review

Child Neurology Open ◽

10.1177/2329048x211036137 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110361

Author(s):

Ashley A. Moeller ◽

Marcia V. Felker ◽

Jennifer A. Brault ◽

Laura C. Duncan ◽

Rizwan Hamid ◽

...

Keyword(s):

Symptom Onset ◽

Huntington Disease ◽

Early Onset ◽

Trinucleotide Repeat ◽

Cerebellar Atrophy ◽

Cag Repeats ◽

Ataxic Gait ◽

Repeat Expansions ◽

Delays In Diagnosis ◽

Juvenile Huntington Disease

Huntington disease (HD) is caused by a pathologic cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the HTT gene. Typical adult-onset disease occurs with a minimum of 40 repeats. With more than 60 CAG repeats, patients can have juvenile-onset disease (jHD), with symptom onset by the age of 20 years. We report a case of a boy with extreme early onset, paternally inherited jHD, with symptom onset between 18 and 24 months. He was found to have 250 to 350 CAG repeats, one of the largest repeat expansions published to date. At initial presentation, he had an ataxic gait, truncal titubation, and speech delay. Magnetic resonance imaging showed cerebellar atrophy. Over time, he continued to regress and became nonverbal, wheelchair-bound, gastrostomy-tube dependent, and increasingly rigid. His young age at presentation and the ethical concerns regarding HD testing in minors delayed his diagnosis.

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Contribution of TMS and TMS-EEG to the Understanding of Mechanisms Underlying Physiological Brain Aging

Brain Sciences ◽

10.3390/brainsci11030405 ◽

2021 ◽

Vol 11 (3) ◽

pp. 405

Author(s):

Andrea Guerra ◽

Lorenzo Rocchi ◽

Alberto Grego ◽

Francesca Berardi ◽

Concetta Luisi ◽

...

Keyword(s):

Evoked Potentials ◽

Brain Aging ◽

Cortical Excitability ◽

Motor Evoked Potentials ◽

Neurological Diseases ◽

Physiological Activity ◽

Neuronal Loss ◽

Normal Brain ◽

Potential Contribution ◽

Brain Degeneration

In the human brain, aging is characterized by progressive neuronal loss, leading to disruption of synapses and to a degree of failure in neurotransmission. However, there is increasing evidence to support the notion that the aged brain has a remarkable ability to reorganize itself, with the aim of preserving its physiological activity. It is important to develop objective markers able to characterize the biological processes underlying brain aging in the intact human, and to distinguish them from brain degeneration associated with many neurological diseases. Transcranial magnetic stimulation (TMS), coupled with electromyography or electroencephalography (EEG), is particularly suited to this aim, due to the functional nature of the information provided, and thanks to the ease with which it can be integrated with behavioral manipulation. In this review, we aimed to provide up to date information about the role of TMS and TMS-EEG in the investigation of brain aging. In particular, we focused on data about cortical excitability, connectivity and plasticity, obtained by using readouts such as motor evoked potentials and transcranial evoked potentials. Overall, findings in the literature support an important potential contribution of TMS to the understanding of the mechanisms underlying normal brain aging. Further studies are needed to expand the current body of information and to assess the applicability of TMS findings in the clinical setting.

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Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

Scientific Reports ◽

10.1038/s41598-021-87097-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yogeeshwar Ajjugal ◽

Narendar Kolimi ◽

Thenmalarchelvi Rathinavelan

Keyword(s):

Rna Binding ◽

Trinucleotide Repeat ◽

Rna Binding Proteins ◽

Fragile X ◽

Repeat Expansion ◽

Mobility Shift ◽

Cgg Repeat ◽

Dna And Rna ◽

Structural Choice ◽

Sense Strand

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

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Autism Profiles of Males With Fragile X Syndrome

American Journal on Mental Retardation ◽

10.1352/2008.113:427-438 ◽

2008 ◽

Vol 113 (6) ◽

pp. 427-438 ◽

Cited By ~ 251

Author(s):

Susan W. Harris ◽

David Hessl ◽

Beth Goodlin-Jones ◽

Jessica Ferranti ◽

Susan Bacalman ◽

...

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Autism Diagnosis ◽

Cgg Repeat ◽

Molecular Features ◽

Fmr1 Mrna ◽

Two Measures ◽

Dsm Iv ◽

Relationship Of ◽

The Relationship

Abstract Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

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