Nature neuroscienceOct 2, 2012

Different roles of ALS-related proteins FUS/TLS and TDP-43 overlap in handling long RNA messages before they become mature

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 25, 2026

Abstract

FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain.

FUS/TLS binding occurs primarily through a GUGGU-binding motif.
A sawtooth-like binding pattern indicates co-transcriptional deposition of FUS/TLS.
Depletion of FUS/TLS affects levels or splicing of over 950 mRNAs, distinct from those affected by TDP-43.
Only 45 RNAs showed reduced abundance after the depletion of either TDP-43 or FUS/TLS.
Reduced expression of certain mRNAs is linked to genes with long introns that are vital for neuronal integrity.

Simplified

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.

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Different roles of ALS-related proteins FUS/TLS and TDP-43 overlap in handling long RNA messages before they become mature

Abstract

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