Current molecular insight to reveal the dynamics of CAG repeating units in spinocerebellar ataxia

Vishwakarma, Priyanka; Muthuswamy, Srinivasan; Agarwal, Sarita

doi:10.5582/irdr.2018.01039

Cited by 9 publications

(10 citation statements)

References 52 publications

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“…Although endogenous nucleic acid sequences do not typically lead to aggregation, they have the potential to form multimeric networks through both canonical and non-canonical base pairing interactions 16 . For example, r(CAG) n and r(GGGGCC) n , both natural sequences related to neurodegenerative diseases (spinocerebellar ataxia 17 and ALS/FTD respectively), phase-separate in vitro at a critical number of repeats, suggesting that they can form multimolecular structures 18 . r(GGGGCC) n , in particular, has previously been shown to arrange into hairpin and G-quadruplex (G4) structures, both of which have exhibited potential involvement in disease progression 19 .…”

mentioning

confidence: 99%

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Raguseo,

Wang,

et al. 2023

Nat Commun

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.

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confidence: 99%

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Raguseo,

Wang,

et al. 2023

Nat Commun

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“…Moreover, a comparison to SCA patients was performed in which a genetic predisposed loss of Purkinje cells occurs [ 23 ]. In several forms of SCA the demise of Purkinje cells is caused by the formation of aggregates of the mutated ataxin-1 protein [ 24 ]. In paraneoplastic cerebellar degeneration more and more evidence of a T-cell mediated Purkinje cell death is accumulating [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Cerebellar presence of immune cells in patients with neuro-coeliac disease

Rouvroye

Bontkes

Bol

et al. 2023

acta neuropathol commun

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Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction was even more prominent with a median reduction of 81.3% compared to NNC. Marked increased numbers of both CD3+ and CD8+ cells were observed in the NeuroCD but not in SCA patients. This coincided with significantly more microglial reactivity in NeuroCD patients. These findings demonstrate that the massive loss of Purkinje cells in the cerebellum of neuro CD patients is accompanied by local innate and T-cell mediated immune responses.

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“…In addition to DNA damage, altered chromatin acetylation, and alterations in transcription, other nuclear processes that may contribute to the pathophysiology of SCAs include nonprotein‐coding repeat expansions that sequester RNA‐binding proteins and induce some SCAs. Repeated cytoplasmic expansions of SCA disease proteins can also result in noncanonical translation, producing polypeptides that are prone to aggregation (Mochel et al, 2020; Vishwakarma et al, 2018).…”

Section: Spinocerebellar Ataxias (Scas)mentioning

confidence: 99%

K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel

Rahman,

Orfali,

Dave

et al. 2023

J of Neuroscience Research

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One group of the K+ ion channels, the small‐conductance Ca2+‐activated potassium channels (KCa2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small‐conductance Ca2+‐activated potassium channels (SK channels) due to their comparatively low single‐channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca2+. According to the phylogenic research done on the KCa2.x channels family, there are three channels' subtypes: KCa2.1, KCa2.2, and KCa2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The KCa2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. KCa2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the KCa2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express KCa2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss‐of‐function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss‐of‐function mutations, which are most likely to induce KCNN2 haploinsufficiency. The KCa2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective KCa2.2 modulators are promising potential therapeutics for SCAs.

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Current molecular insight to reveal the dynamics of CAG repeating units in spinocerebellar ataxia

Cited by 9 publications

References 52 publications

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Cerebellar presence of immune cells in patients with neuro-coeliac disease

K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel

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Current molecular insight to reveal the dynamics of CAG repeating units in spinocerebellar ataxia

Cited by 9 publications

References 52 publications

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Cerebellar presence of immune cells in patients with neuro-coeliac disease

KCa2.2 (KCNN2): A physiologically and therapeutically important potassium channel

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K_Ca2.2 (KCNN2): A physiologically and therapeutically important potassium channel