Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.
Abstract
Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration.
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Linked Datasets (2)
Gene Expression Signatures of Motor Neuron Populations Isolated from Sporadic ALS
Homo sapiens63 data files
| File | Type | Size |
|---|---|---|
| 10C.fastq.gz | RNA-Seq | 511.2 MB |
| 10C.fastq.gz | RNA-Seq | 511.2 MB |
| 10C.fastq.gz | RNA-Seq | 511.2 MB |
| 16A.fastq.gz | RNA-Seq | 884.9 MB |
| 16A.fastq.gz | RNA-Seq | 884.9 MB |
| 16A.fastq.gz | RNA-Seq | 884.9 MB |
| 21A.fastq.gz | RNA-Seq | 987.5 MB |
| 21A.fastq.gz | RNA-Seq | 987.5 MB |
| 21A.fastq.gz | RNA-Seq | 987.5 MB |
| 27A.fastq.gz | RNA-Seq | 722.2 MB |
| 27A.fastq.gz | RNA-Seq | 722.2 MB |
| 27A.fastq.gz | RNA-Seq | 722.2 MB |
| 34A.fastq.gz | RNA-Seq | 930.8 MB |
| 34A.fastq.gz | RNA-Seq | 930.8 MB |
| 34A.fastq.gz | RNA-Seq | 930.8 MB |
| 39C.fastq.gz | RNA-Seq | 1020.0 MB |
| 39C.fastq.gz | RNA-Seq | 1020.0 MB |
| 39C.fastq.gz | RNA-Seq | 1020.0 MB |
| 44C.fastq.gz | RNA-Seq | 861.3 MB |
| 44C.fastq.gz | RNA-Seq | 861.3 MB |
| 44C.fastq.gz | RNA-Seq | 861.3 MB |
| 48A.fastq.gz | RNA-Seq | 299.4 MB |
| 48A.fastq.gz | RNA-Seq | 299.4 MB |
| 48A.fastq.gz | RNA-Seq | 299.4 MB |
| 60A.fastq.gz | RNA-Seq | 777.3 MB |
| 60A.fastq.gz | RNA-Seq | 777.3 MB |
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| 62A.fastq.gz | RNA-Seq | 828.2 MB |
| 62A.fastq.gz | RNA-Seq | 828.2 MB |
| 62A.fastq.gz | RNA-Seq | 828.2 MB |
| 63A.fastq.gz | RNA-Seq | 751.5 MB |
| 65C.fastq.gz | RNA-Seq | 766.3 MB |
| 65C.fastq.gz | RNA-Seq | 766.3 MB |
| 65C.fastq.gz | RNA-Seq | 766.3 MB |
| 67C.fastq.gz | RNA-Seq | 1.0 GB |
| 67C.fastq.gz | RNA-Seq | 1.0 GB |
| 67C.fastq.gz | RNA-Seq | 1.0 GB |
| 76C.fastq.gz | RNA-Seq | 1.1 GB |
| 76C.fastq.gz | RNA-Seq | 1.1 GB |
| 76C.fastq.gz | RNA-Seq | 1.1 GB |
| 78C.fastq.gz | RNA-Seq | 531.1 MB |
| 78C.fastq.gz | RNA-Seq | 531.1 MB |
| 78C.fastq.gz | RNA-Seq | 531.1 MB |
| 79A.fastq.gz | RNA-Seq | 1.0 GB |
| 79A.fastq.gz | RNA-Seq | 1.0 GB |
| 79A.fastq.gz | RNA-Seq | 1.0 GB |
| 82A.fastq.gz | RNA-Seq | 981.6 MB |
| 82A.fastq.gz | RNA-Seq | 981.6 MB |
| 82A.fastq.gz | RNA-Seq | 981.6 MB |
| 84A.fastq.gz | RNA-Seq | 241.4 MB |
| 85A.fastq.gz | RNA-Seq | 946.3 MB |
| 85A.fastq.gz | RNA-Seq | 946.3 MB |
| 85A.fastq.gz | RNA-Seq | 946.3 MB |
| 88C.fastq.gz | RNA-Seq | 531.1 MB |
| 89A.fastq.gz | RNA-Seq | 471.7 MB |
| SRR3038260 | RNA-Seq | 531.1 MB |
| SRR3038260 | RNA-Seq | 531.1 MB |
| SRR3038263 | RNA-Seq | 751.5 MB |
| SRR3038263 | RNA-Seq | 751.5 MB |
| SRR3038264 | RNA-Seq | 241.4 MB |
| SRR3038264 | RNA-Seq | 241.4 MB |
| SRR3038265 | RNA-Seq | 471.7 MB |
| SRR3038265 | RNA-Seq | 471.7 MB |
Transcriptome-pathology correlations predict CSNK1E-mediated TDP-43 phosphorylation in sporadic amyotrophic lateral sclerosis
Homo sapiens20 data files
| File | Type | Size |
|---|---|---|
| RB_CTRL39_INPUT_S69_L007_R1_001.fastq.gz | RIP-Seq | 903.8 MB |
| RB_CTRL39_INPUT_S69_L007_R1_001.fastq.gz | RIP-Seq | 903.8 MB |
| RB_CTRL39_IP_S70_L007_R1_001.fastq.gz | RIP-Seq | 863.1 MB |
| RB_CTRL4_INPUT_S67_L007_R1_001.fastq.gz | RIP-Seq | 1.1 GB |
| RB_CTRL4_INPUT_S67_L007_R1_001.fastq.gz | RIP-Seq | 1.1 GB |
| RB_CTRL4_IP_S68_L007_R1_001.fastq.gz | RIP-Seq | 888.4 MB |
| RB_CTRL4_IP_S68_L007_R2_001.fastq.gz | RIP-Seq | 888.4 MB |
| RB_sALS30_INPUT_S71_L007_R1_001.fastq.gz | RIP-Seq | 942.7 MB |
| RB_sALS30_INPUT_S71_L007_R1_001.fastq.gz | RIP-Seq | 942.7 MB |
| RB_sALS30_IP_S72_L007_R1_001.fastq.gz | RIP-Seq | 1.0 GB |
| RB_sALS30_IP_S72_L007_R1_001.fastq.gz | RIP-Seq | 1.0 GB |
| RB_sALS32_INPUT_S75_L007_R1_001.fastq.gz | RIP-Seq | 906.8 MB |
| RB_sALS32_INPUT_S75_L007_R1_001.fastq.gz | RIP-Seq | 906.8 MB |
| RB_sALS32_IP_S76_L007_R1_001.fastq.gz | RIP-Seq | 859.0 MB |
| RB_sALS32_IP_S76_L007_R1_001.fastq.gz | RIP-Seq | 859.0 MB |
| RB_sALS33_INPUT_S77_L007_R1_001.fastq.gz | RIP-Seq | 833.9 MB |
| RB_sALS33_IP_S78_L007_R1_001.fastq.gz | RIP-Seq | 775.6 MB |
| SRR5988191 | RIP-Seq | 863.1 MB |
| SRR5988194 | RIP-Seq | 775.6 MB |
| SRR5988199 | RIP-Seq | 833.9 MB |
Potentially Related Datasets (1)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
eCLIP experiment on K562 against TDP43