Journal
ACTA NEUROPATHOLOGICA
Volume 136, Issue 3, Pages 405-423Publisher
SPRINGER
DOI: 10.1007/s00401-018-1870-7
Keywords
ALS; Neurodegeneration; Laser capture microdissection; RNA-seq; RNA; Gene-expression; TDP-43; Casein kinase; Motor neuron; Sporadic disease
Categories
Funding
- National Institute of Health [HG004659, NS075449, U54HG007005]
- ALS Association
- Target ALS
- National Institutes of Health [NS051738]
- Microsoft Research
- Moyer Foundation
- Benaroya Foundation
- Pam Golden
- Wyckoff family
- Bavaria California Technology Center (BaCaTeC) [8 [2015-2]]
- German Federal Ministry of Education and Research (BMBF) [01GQ113]
- Bavarian Ministry of Education and Culture, Science, and the Arts in the framework of the Bavarian Research Network Induced Pluripotent Stem Cells ForIPS
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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.
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