Triplet Repeat Diseases

Guyenet, Stephan J.; Spada, Albert R. La

doi:10.1002/3527600906.mcb.200500027

Cited by 4 publications

(3 citation statements)

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“…PolyQ disorders include the following diseases: Huntington disease, dentatorubural-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3/ Machado-Joseph disease (MJD), SCA6, SCA7, SCA17, and SBMA. Although the pathogenetic mechanism of PolyQ disorders has not been fully understood, most evidence suggests that abnormally elongated CAG repeats generate mutant proteins with abnormally elongated polyglutamates, which cause neurotoxicity through an abnormal conformation and misfold [7,8]. With the exception of X-linked SBMA, the inheritance pattern of PolyQ disorders is autosomal dominant, and many polyQ disorders display "anticipation", which is defined as more enhanced disease severity in successive generations of patients with more elongated CAG repeats and earlier disease onset [9].…”

Section: Polyq Disordersmentioning

confidence: 99%

“…In 2019, three diseases (neuronal intranuclear inclusion disease [NIID], oculopharyngeal myopathy with leukoencephalopathy [OPML], and oculopharyngodistal myopathy-1 [OPDM1]) were newly recognized as TRDs [6], and now there are more than 20 TRDs with frequent abnormal neuroimaging findings. TRDs are divided into the following four groups, depending on the pathomechanisms, although the pathomechanisms of several diseases remain unelucidated [7]:…”

Section: Introductionmentioning

confidence: 99%

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Clinical and neuroimaging review of triplet repeat diseases

Kurokawa

Mitsutake

et al. 2022

Jpn J Radiol

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Triplet repeat diseases (TRDs) refer to a group of diseases caused by three nucleotide repeats elongated beyond a pathologic threshold. TRDs are divided into the following four groups depending on the pathomechanisms, although the pathomechanisms of several diseases remain unelucidated: polyglutamine disorders, caused by a pathologic repeat expansion of CAG (coding the amino acid glutamine) located within the exon; loss-of-function repeat disorders, characterized by the common feature of a loss of function of the gene within which they occur; RNA gain-of-function disorders, involving the production of a toxic RNA species; and polyalanine disorders, caused by a pathologic repeat expansion of GCN (coding the amino acid alanine) located within the exon. Many of these TRDs manifest through neurologic symptoms; moreover, neuroimaging, especially brain magnetic resonance imaging, plays a pivotal role in the detection of abnormalities, differentiation, and management of TRDs. In this article, we reviewed the clinical and neuroimaging features of TRDs. An early diagnosis of TRDs through clinical and imaging approaches is important and may contribute to appropriate medical intervention for patients and their families.

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Section: Polyq Disordersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical and neuroimaging review of triplet repeat diseases

Kurokawa

Mitsutake

et al. 2022

Jpn J Radiol

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“…Except for SBMA, which is X-linked, these disorders are inherited in an autosomal-dominant fashion. SBMA has a prevalence of about 1 in 50,000 males, HD, 1 per 15,000 persons worldwide, and, all together, the prevalence of the SCAs has been estimated at ∼3 per 100,000 (Guyenet and La Spada, 2006; Truant et al, 2006). The polyglutamine diseases share several features including late-onset, progressive neurodegeneration, accumulation of misfolded polyQ proteins in the cytoplasm or nucleus of neurons, and a positive correlation between CAG repeat length and disease severity (Parodi and Pennuto, 2011; Tanaka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

Beitel¹,

Alvarado²,

Mokhtar³

et al. 2013

Front. Neurol.

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Spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA.

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Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic development in Huntington's disease

Joshi

Thakur

2014

Journal of Peptide Science

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Huntington's and eight other neurodegenerative diseases occur because of CAG repeat expansion mutation culminating into an expanded polyglutamine tract in respective protein. In Huntington's disease (HD), a number of CAG repeats beyond normal repeat length (>36) lead to the formation of mutant protein, the proteolytic cleavage of which induces aggregation in polyglutamine length-dependent manner. The neurodegeneration in this disease is linked to aggregation, and its inhibition is a potential approach for therapeutic development. Although peptides and other molecules have been developed for inhibiting aggregation, peptides in general are susceptible to degradation in vivo conditions. To understand their clinical significance, they also need to be delivered through blood-brain barrier. Here, for the first time, we have synthesized poly-d,l-lactide-co-glycolide nanoparticles containing a polyglutamine aggregation inhibitor peptide PGQ9 [P(2) ], by nanoprecipitation method. This process yielded less than 200 nm spherical nanoparticles with uniform distribution. Characterization studies by infrared spectroscopy-based and HPLC-based assays show the presence of PGQ9 [P(2) ] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ9 [P(2) ] by erosion and diffusion processes. When the PGQ9 [P(2) ]-loaded nanoparticles are incubated with aggregation-prone Q35 P10 peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q35 P10 aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD.

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Triplet Repeat Diseases

Cited by 4 publications

References 100 publications

Clinical and neuroimaging review of triplet repeat diseases

Clinical and neuroimaging review of triplet repeat diseases

Mechanisms Mediating Spinal and Bulbar Muscular Atrophy: Investigations into Polyglutamine-Expanded Androgen Receptor Function and Dysfunction

Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic development in Huntington's disease

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