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Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Lee FC, Masino L, Qi YA, Bryce-Smith S, Bampton A, Gatt A, Phatnani H, NYGC ALS Consortium, Schiavo G, Fisher EM, Raj T, Secrier M, Lashley T, Ule J, Buratti E, Humphrey J, Ward ME, Fratta P. Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing 2 and loss upon TDP-43 mislocalization. bioRxiv. April 4, 2021. BioRxiv.
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Johns Hopkins
Recent studies from human neurodegenerative disease strongly support the notion that nuclear depletion of TDP-43, and the resulting compromised splicing repression, represents an early event that contributes to disease pathogenesis. First, we documented loss of splicing repression in brains of ALS-FTD cases (Ling et al., 2015). Second, TDP-43 nuclear depletion in brain neurons has been reported at the presymptomatic stage in a C9ORF72-linked FTD-ALS patient, suggesting that loss of splicing repression represents an early event in disease progression (Vatsavayai et al., 2016). Third, incorporation of nonconserved cryptic exons can also be found in cases of Alzheimer’s disease with TDP-43 pathology in the absence of cytoplasmic inclusions (Sun et al., 2017). Fourth, ALS-linked mutant forms of TDP-43 fail to repress nonconserved cryptic exons (e.g., Stathmin-2), independent of TDP-43 cytoplasmic aggregation (Klim et al., 2019; Melamed et al., 2019).
Identification of UNC13A as a TDP-43 cryptic exon target that is linked to risk SNPs for ALS-FTD in these two manuscripts provides further support for the idea that loss of TDP-43 splicing repression of cryptic exons drives disease or influence its progression.
While depletion of TDP-43 would lead to inclusion of a host of cryptic exons, it is also possible that alterations in TDP-43 binding sites (UG rich element) could potentially impact on cryptic exon inclusion, as demonstrated by these two studies, for the SNP within a cryptic exon of UNC13A. As a “guardian of the transcriptome,” TDP-43, represses nonconserved cryptic exons, many of which reside within introns. This raises the important question as to whether other cryptic exon targets are also subject to influence of risk SNPs for ALS-FTD.
Based on first principals, it is conceivable that a series of other cryptic exons could be influenced by SNPs, which often reside within introns, that modify the binding of TDP-43. Positive outcomes from future studies should validate this notion.
References:
Ling JP, Pletnikova O, Troncoso JC, Wong PC. NEURODEGENERATION. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015 Aug 7;349(6248):650-5. PubMed.
Vatsavayai SC, Yoon SJ, Gardner RC, Gendron TF, Vargas JN, Trujillo A, Pribadi M, Phillips JJ, Gaus SE, Hixson JD, Garcia PA, Rabinovici GD, Coppola G, Geschwind DH, Petrucelli L, Miller BL, Seeley WW. Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain. 2016 Dec;139(Pt 12):3202-3216. Epub 2016 Oct 22 PubMed.
Sun M, Bell W, LaClair KD, Ling JP, Han H, Kageyama Y, Pletnikova O, Troncoso JC, Wong PC, Chen LL. Cryptic exon incorporation occurs in Alzheimer's brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. Acta Neuropathol. 2017 Jun;133(6):923-931. Epub 2017 Mar 22 PubMed.
Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ, Gamage KK, Kirchner R, Moccia R, Cassel SH, Chen K, Wainger BJ, Woolf CJ, Eggan K. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci. 2019 Feb;22(2):167-179. Epub 2019 Jan 14 PubMed.
Melamed Z, López-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, Freyermuth F, McMahon MA, Beccari MS, Artates JW, Ohkubo T, Rodriguez M, Lin N, Wu D, Bennett CF, Rigo F, Da Cruz S, Ravits J, Lagier-Tourenne C, Cleveland DW. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019 Feb;22(2):180-190. Epub 2019 Jan 14 PubMed.
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