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

Krach F, Batra R, Wheeler EC, Vu AQ, Wang R, Hutt K, Rabin SJ, Baughn MW, Libby RT, Diaz-Garcia S, Stauffer J, Pirie E, Saberi S, Rodriguez M, Madrigal AA, Kohl Z, Winner B, Yeo GW, Ravits J (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Acta Neuropathologica Springer Verlag (Germany)

Book Volume: 136

Pages Range: 405-423

Journal Issue: 3

DOI: 10.1007/s00401-018-1870-7

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 1 epsilon (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.

Authors with CRIS profile

Zacharias Kohl Department of Molecular Neurology Beate Winner Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

University of California, San Diego US United States (USA) (US) Benaroya Research Institute US United States (USA) (US)

How to cite

APA:

Krach, F., Batra, R., Wheeler, E.C., Vu, A.Q., Wang, R., Hutt, K.,... Ravits, J. (2018). Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS. Acta Neuropathologica, 136(3), 405-423. https://doi.org/10.1007/s00401-018-1870-7

MLA:

Krach, Florian, et al. "Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS." Acta Neuropathologica 136.3 (2018): 405-423.

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