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Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Florian Krach, Ranjan Batra, Emily C Wheeler, Anthony Q Vu, Ruth Wang, Kasey Hutt, Stuart J Rabin, Michael W Baughn, Ryan T Libby, Sandra Diaz-Garcia, Jennifer Stauffer, Elaine Pirie, Shahram Saberi, Maria Rodriguez, Assael A Madrigal, Zacharias Kohl, Beate Winner, Gene W Yeo, John Ravits

Acta neuropathologica · 2018 · Vol. 136 (3) · pp. 405-423

PubMed ↗ DOI ↗ PMC full text ↗

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.

Linked datasets 2

GSE76220 GSE · via ncbi_elink
GEO ↗

Gene Expression Signatures of Motor Neuron Populations Isolated from Sporadic ALS

Homo sapiens

46 data files
FileTypeSize
10C.fastq.gz RNA-Seq 511.2 MB
16A.fastq.gz RNA-Seq 884.9 MB
21A.fastq.gz RNA-Seq 987.5 MB
27A.fastq.gz RNA-Seq 722.2 MB
34A.fastq.gz RNA-Seq 930.8 MB
39C.fastq.gz RNA-Seq 1020.0 MB
44C.fastq.gz RNA-Seq 861.3 MB
48A.fastq.gz RNA-Seq 299.4 MB
60A.fastq.gz RNA-Seq 777.3 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
67C.fastq.gz RNA-Seq 1.0 GB
76C.fastq.gz RNA-Seq 1.1 GB
78C.fastq.gz RNA-Seq 531.1 MB
79A.fastq.gz RNA-Seq 1.0 GB
82A.fastq.gz RNA-Seq 981.6 MB
84A.fastq.gz RNA-Seq 241.4 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
SRR3038253_GSM1977027 RNA-Seq 511.0 MB
SRR3038254_GSM1977028 RNA-Seq 766.0 MB
SRR3038255_GSM1977029 RNA-Seq 531.0 MB
SRR3038256_GSM1977030 RNA-Seq 1019.0 MB
SRR3038257_GSM1977031 RNA-Seq 1.0 GB
SRR3038258_GSM1977032 RNA-Seq 1.1 GB
SRR3038259_GSM1977033 RNA-Seq 861.0 MB
SRR3038260 RNA-Seq 531.1 MB
SRR3038260_GSM1977034 RNA-Seq 531.0 MB
SRR3038261_GSM1977035 RNA-Seq 777.0 MB
SRR3038262_GSM1977036 RNA-Seq 828.0 MB
SRR3038263 RNA-Seq 751.5 MB
SRR3038263_GSM1977037 RNA-Seq 751.0 MB
SRR3038264 RNA-Seq 241.4 MB
SRR3038264_GSM1977038 RNA-Seq 241.0 MB
SRR3038265 RNA-Seq 471.7 MB
SRR3038265_GSM1977039 RNA-Seq 471.0 MB
SRR3038266_GSM1977040 RNA-Seq 987.0 MB
SRR3038267_GSM1977041 RNA-Seq 930.0 MB
SRR3038268_GSM1977042 RNA-Seq 1.0 GB
SRR3038269_GSM1977043 RNA-Seq 981.0 MB
SRR3038270_GSM1977044 RNA-Seq 884.0 MB
SRR3038271_GSM1977045 RNA-Seq 722.0 MB
SRR3038272_GSM1977046 RNA-Seq 299.0 MB
SRR3038273_GSM1977047 RNA-Seq 946.0 MB
GSE103225 GSE · via ncbi_elink
GEO ↗

Transcriptome-pathology correlations predict CSNK1E-mediated TDP-43 phosphorylation in sporadic amyotrophic lateral sclerosis

Homo sapiens

24 data files
FileTypeSize
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_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_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_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
SRR5988190_GSM2758478 RIP-Seq 888.0 MB
SRR5988191 RIP-Seq 863.1 MB
SRR5988191_GSM2758479 RIP-Seq 863.0 MB
SRR5988192_GSM2758480 RIP-Seq 1.0 GB
SRR5988193_GSM2758481 RIP-Seq 858.0 MB
SRR5988194 RIP-Seq 775.6 MB
SRR5988194_GSM2758482 RIP-Seq 775.0 MB
SRR5988195_GSM2758483 RIP-Seq 1.1 GB
SRR5988196_GSM2758484 RIP-Seq 903.0 MB
SRR5988197_GSM2758485 RIP-Seq 942.0 MB
SRR5988198_GSM2758486 RIP-Seq 906.0 MB
SRR5988199 RIP-Seq 833.9 MB
SRR5988199_GSM2758487 RIP-Seq 833.0 MB

Potentially related datasets 3

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.

Accession Source Title
ENCSR584TCR ENCSR · ENCODE eCLIP experiment on K562 against TDP43
GSE103225 GSE · GEO GEO ↗ Transcriptome-pathology correlations predict CSNK1E-mediated TDP-43 phosphorylation in sporadic amyotrophic lateral sclerosis
GSE76220 GSE · GEO GEO ↗ Gene Expression Signatures of Motor Neuron Populations Isolated from Sporadic ALS

Analysis pipelines 2

Pipeline Assay Steps Dataset
GSE103225 eCLIP Data Processing geo_data_processing eCLIP 32 GSE103225
GSE76220 HITS-CLIP Data Processing geo_data_processing HITS-CLIP 5 GSE76220
Funding 6 grants
Grant Funder
R01 HG004659 NHGRI NIH HHS (United States)
U54 HG007005 NHGRI NIH HHS (United States)
R01 NS075449 NINDS NIH HHS (United States)
R21 NS051738 NINDS NIH HHS (United States)
U56HG007005 NIH HHS (United States)
01GQ113 Bundesministerium für Bildung und Forschung (International)