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AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Addition]

ABSTRACT: AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Addition]

PROVIDER: PRJNA1043564 | ENA |

REPOSITORIES: ENA

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AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Addition]

Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by a biallelic, non-reference pentameric CCCTT(AAGGG) repeat expansion within the second intron of replication factor complex subunit 1 (RFC1). While rare compound heterozygous CANVAS cases harbor RFC1 loss-of-function mutations alongside monoallelic repeat-expansions, RFC1 expression is maintained at normal levels in the presence of biallelic expanded repeats. To investigate how these pentameric repeats cause disease, we generated CANVAS patient iPSC derived neurons and utilized calcium imaging and transcriptomic analysis to define repeat elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. Importantly, these deficits were not replicated by knockdown of RFC1 in control neurons and showed incomplete or no rescue upon over-expression of RFC1. These findings support a repeat-dependent and RFC1-independent mechanism as the underlying cause of neurodegeneration in CANVAS, with important implications for therapeutic development in this currently untreatable condition.

2024-09-01 | GSE248344 | GEO

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Knockdown]

2024-09-01 | GSE248343 | GEO

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [CANVAS_Control_Isogenic]

2024-09-01 | GSE248342 | GEO

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Knockdown]

Project description:AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Knockdown]

| PRJNA1043563 | ENA

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [CANVAS_Control_Isogenic]

Project description:AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [CANVAS_Control_Isogenic]

| PRJNA1043562 | ENA

AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons

Project description:AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons

| PRJNA1043558 | ENA

AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-01 | GSE248345 | GEO

Transcriptomic analysis of iPSC-derived motor neurons from ALS patients carrying ATXN2 intermediate repeat expansions and healthy controls

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we developed a human iPSC-derived model to investigate whether motor neurons derived from ALS patients carrying ATXN2 intermediate repeat expansions are transcriptomically distinct from healthy controls. For that, we performed RNA sequencing of motor neurons derived from 5 ATXN2-ALS iPSC lines and 5 healthy controls (HC).

2024-07-16 | GSE224578 | GEO

RNA-dependent epigenetic silencing directs transcriptional down regulation caused by intronic repeat expansions

Project description:Transcriptional down regulation caused by intronic triplet repeat expansions underlies diseases such as Friedreich?s ataxia. This down regulation of gene expression is coupled with epigenetic changes but the underlying mechanisms are unknown. Here, we show that an intronic TTC/GAA triplet expansion within the IIL1 gene of Arabidopsis thaliana results in accumulation of 24-nt siRNAs and repressive histone marks at the IIL1 locus, which in turn causes its transcriptional down regulation and an associated phenotype. Knocking down DICER LIKE-3 (DCL3), which produces 24-nt siRNAs, suppressed transcriptional down regulation of IIL1 and the expansion-associated phenotype. Furthermore, knocking down additional components of the RNA-dependent DNA Methylation (RdDM) pathway, also suppressed both transcriptional down regulation of IIL1 and the repeat expansion associated phenotype. Thus our results show that triplet repeat expansions can lead to local siRNA biogenesis, which in turn down regulates transcription through an RdDM-dependent epigenetic modification.

2018-07-25 | GSE113923 | GEO

Single-cell RNA sequencing analysis of iPSC-derived motor neurons from an ALS patient carrying ATXN2 intermediate repeat expansions and a healthy control

Project description:Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are a strong genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we developed a human iPSC-derived model to investigate whether motor neurons derived from an ALS patient carrying ATXN2 intermediate repeat expansions (ALS-G) are transcriptomically distinct from a healthy control(OH2.6). For that, we generated a single cell RNA sequencing dataset consisting of a total of 384 cells.

2024-07-16 | GSE224582 | GEO

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