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ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function

ABSTRACT: ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function

PROVIDER: PRJNA805280 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17978864_1.fastq.gz	Fastqsanger.gz
	SRR17978864_2.fastq.gz	Fastqsanger.gz
	SRR17978865_1.fastq.gz	Fastqsanger.gz
	SRR17978865_2.fastq.gz	Fastqsanger.gz
	SRR17978866_1.fastq.gz	Fastqsanger.gz

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ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RIP-seq]

Project description:ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RIP-seq]

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ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RNA-seq]

Project description:ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RNA-seq]

| PRJNA805277 | ENA

ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function

Project description:Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39-amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C-terminus of mutant KIF5A results in a constitutively active state. Further, mutant KIF5A possesses novel protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.

2022-06-09 | PXD031012 | Pride

ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RIP-seq]

Project description:Purpose: The goal of this study is to identify and compare the mRNA interactomes of WT and ALS-related mutant (d27) KIF5A Methods: RNA samples were extracted and sequenced on an Illumina NovaSeq6000 instrument at the Yale Center for Genome Analysis. The sample sequence quality control check was performed using FastQc. The STAR aligner program was used for read mapping with reference file and HTSeq was used to count the reads for each transcript in strand specific mode. The Differential expression analysis was performed using the DESeq2 package to compare the gene expression profiles between wild type and mutant was performed using the Wald test to generate p-values and Log2 fold changes. The STAR aligned RNA Sequence sample bam files were used to detect differential alternative splicing events with the Multivariate Analysis of Transcript Splicing (MATS) method. Pathway analysis was performed with Metascape Results: With the RNA RIP Sequence pipeline, we analyzed the RNA Sequence from SKNAS cells expressing WT KIF5A and cells epxressing the KIF5a ALS delta27 mutant. We identified 1,184 transcripts that displayed enriched binding to KIF5AΔExon27 and 303 that showed decreased binding to KIF5A ΔExon27. Pathway analysis revealed several categories related to ALS pathogenesis. KIF5AΔExon27 enriched pathways included NGF-stimulated transcription, which is related to neurite outgrowth. Pathways that were underrepresented in KIF5A ΔExon27 samples compared to KIF5AWT included interactions between L1 and Ankyrins, synapse assembly, and potassium channels. The results demonstrate that mutations in KIF5A can result in altered interaction with proteins and RNA associated with ALS-related pathways. Conclusions: Our analysis demonstates that ALS-related mutant KIF5A (d27) has altered RNA interactions compared to the WT protein.

2022-02-17 | GSE196538 | GEO

ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function [RNA-seq]

Project description:Purpose: The goal of this study was to identify gene expression changes in iMNs containing a patient KIF5a mutation compared to an isogenic control. Further, splicing changes were evaluated in the mutant vs WT sample. Methods: RNA samples were extracted and sequenced on an Illumina NovaSeq6000 instrument at the Yale Center for Genome Analysis. The sample sequence quality control check was performed using FastQc. The STAR aligner program was used for read mapping with reference file and HTSeq was used to count the reads for each transcript in strand specific mode. The Differential expression analysis was performed using the DESeq2 package to compare the gene expression profiles between wild type and mutant was performed using the Wald test to generate p-values and Log2 fold changes. The STAR aligned RNA Sequence sample bam files were used to detect differential alternative splicing events with the Multivariate Analysis of Transcript Splicing (MATS) method. Pathway analysis was performed with Metascape Results: With the RNA Sequence pipeline, we analyzed the RNA Sequence from wild-type parental line (Iso Control) and the heterozygous mutant line (KIF5AR1007K). The RNA Sequence analysis of the iMNs revealed 57 genes displaying altered expression. Using the method, Multivariate Analysis of Transcript Splicing (MATS), we identified 1,919 transcripts with altered splicing compared to the isogenic control iMNs. Of these, 1,000 exons showed decreased skipping, while 919 showed increased skipping in KIF5AR1007K lines. Pathway analysis of each of these groups suggests that this group of altered genes, as a whole, represents cytoskeletal and transport defects in the cell, both of which are hallmarks of neurodegenerative disease.

2022-02-17 | GSE196537 | GEO

ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function.

Project description: Not available

| S-EPMC9134378 | biostudies-literature

ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function

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

2022-02-17 | GSE196539 | GEO

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Project description:Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

2026-03-11 | GSE302774 | GEO

Profiling Kif5A RNA targets in sensory neuron axons

Project description:We previously identified that the RNA binding protein Nucleolin is localized to axons of DRG sensory neurons by interaction with the molecular motor Kinesin-1 (Kif5A) and subsequently localizes importin beta1 mRNA there (Perry et al., 2016). To further identify additional RNAs that are localized to axons in a similar mechanism, we immunopercipitated Kif5A from dorsal roots (centrally projecting axons) or Sciatic nerves (peripherally projecting axons), isolated the bound RNA and sequnced it.

2021-07-23 | GSE142099 | GEO

Profiling Kif5A RNA targets in sensory neuron axons

Project description:Profiling Kif5A RNA targets in sensory neuron axons

| PRJNA595899 | ENA