Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

Topic: Brain proteins, microglia and lab models

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.

Key findings

• We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif.

Why it matters

In mouse and human brain, FUS/TLS bound RNAs from more than 5,500 genes, and depleting it from the adult nervous system altered the levels or splicing of more than 950 mRNAs, most distinct from RNAs dependent on TDP-43. Only 45 RNAs were reduced after depletion of either protein, including mRNAs from genes with exceptionally long introns, supporting a common loss-of-function pathway as one component underlying motor neuron death.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nn.3230
• PubMed: 23023293
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{lagiertourenne2012-23023293,
  author  = {Lagier-Tourenne, C. and Polymenidou, M. and Hutt, K. R. and Vu, A. Q. and Baughn, M. and Huelga, S. C. and Clutario, K. M. and Ling, S. C. and others},
  title   = {{Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs}},
  journal = {Nature neuroscience},
  year    = {2012},
  doi     = {10.1038/nn.3230},
  pmid    = {23023293},
  url     = {https://doi.org/10.1038/nn.3230}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• A new subtype of frontotemporal lobar degeneration with FUS pathology Brain : a journal of neurology · 2009-08-11 · usefulness score 58/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• FUS pathology in basophilic inclusion body disease Acta neuropathologica · 2009-10-15 · usefulness score 51/100 · Brain tissue and pathology
• Understanding the role of TDP-43 and FUS/TLS in ALS and beyond Current opinion in neurobiology · 2011-08-02 · usefulness score 48/100 · Brain tissue and pathology
• TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells The Journal of biological chemistry · 2012-03-16 · usefulness score 47/100 · Brain tissue and pathology

Later studies that cite this one

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• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations Neuron · 2014-02-01 · usefulness score 55/100 · Lewy body dementia
• FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons Nature communications · 2017-03-30 · usefulness score 54/100 · Lewy body dementia
• Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration Proceedings of the National Academy of Sciences of the United States of America · 2013-10-29 · usefulness score 53/100 · Lewy body dementia
• Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies Journal of neurochemistry · 2016-06-15 · usefulness score 51/100 · Brain tissue and pathology
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis Frontiers in molecular neuroscience · 2019-02-14 · usefulness score 50/100 · Lewy body dementia

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• Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS PLoS biology · 2011-04-26 · usefulness score 52/100
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation Nature communications · 2017-06-29 · usefulness score 55/100
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
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