Abstract
Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.
Highlights
Accumulation of TAR DNA-binding protein 43 (TDP-43) containing cytoplasmic inclusions is a shared pathological hallmark in a broad spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease [1]
Because reads could potentially map to many regions, we first used an analysis in which each location was weighted based on the number of alignments (Figs. 1A,B) see methods)
This analysis method (MULTI), which included both unique and multi mapped reads, assigns an enrichment level for each element, but does not distinguish contributions of individual instances of each element. This method can potentially include effects from transposable elements (TEs) that are difficult to map with short read sequence, a disadvantage is that it does not distinguish which instances of a given TE are detected
Summary
Accumulation of TAR DNA-binding protein 43 (TDP-43) containing cytoplasmic inclusions is a shared pathological hallmark in a broad spectrum of neurodegenerative disorders, including ALS, FTLD and Alzheimer’s disease [1]. Mutations in this multifunctional RNA binding protein are known to underlie some familial and sporadic cases of ALS [1]. We included sequences that map to multiple locations and examined reads that align to TEs. Our analyses lead to the striking hypothesis that TE over-expression may contribute to TDP-43 mediated neurodegeneration
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