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. 2024 Mar 27;19(1):29.
doi: 10.1186/s13024-024-00718-8.

HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

Anna Calliari #  1 , Lillian M Daughrity #  1 , Ellen A Albagli  1 , Paula Castellanos Otero  1 , Mei Yue  1 , Karen Jansen-West  1 , Naeyma N Islam  1 , Thomas Caulfield  1 , Bailey Rawlinson  1 , Michael DeTure  1   2 , Casey Cook  1   2 , Neill R Graff-Radford  3 , Gregory S Day  3 , Bradley F Boeve  4 , David S Knopman  4 , Ronald C Petersen  4 , Keith A Josephs  4 , Björn Oskarsson  3 , Aaron D Gitler  5 , Dennis W Dickson  1   2 , Tania F Gendron  1   2 , Mercedes Prudencio  1   2 , Michael E Ward  6   7 , Yong-Jie Zhang  8   9 , Leonard Petrucelli  10   11
Affiliations

HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

Anna Calliari et al. Mol Neurodegener. .

Erratum in

  • Correction: HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases.
    Calliari A, Daughrity LM, Albagli EA, Castellanos Otero P, Yue M, Jansen-West K, Islam NN, Caulfield T, Rawlinson B, DeTure M, Cook C, Graff-Radford NR, Day GS, Boeve BF, Knopman DS, Petersen RC, Josephs KA, Oskarsson B, Gitler AD, Dickson DW, Gendron TF, Prudencio M, Ward ME, Zhang YJ, Petrucelli L. Calliari A, et al. Mol Neurodegener. 2024 Jul 27;19(1):56. doi: 10.1186/s13024-024-00744-6. Mol Neurodegener. 2024. PMID: 39068448 Free PMC article. No abstract available.

Abstract

This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.

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Conflict of interest statement

B.F.B. receives institutional research grant support from Alector, Biogen, Transposon, Cognition Therapeutics, and GE Healthcare. B.F.B. receives an honorarium for SAB activities for the Tau Consortium. L.P. is a consultant for Expansion Therapeutics. D.S.K. serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. D.S.K. served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. D.S.K. is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. D.S.K. has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. D.S.K. attended an Eisai advisory board meeting for lecanemab. A.D.G. is a scientific founder of Maze Therapeutics.

Figures

Fig. 1
Fig. 1
HDGFL2-CE proteins are increased in brain regions with TDP-43 pathology in FTLD-TDP and AD-TDP, and distinguish these TDP-43 proteinopathies from non-TDP-43 controls. Immunoassay quantification of HDGFL2-CE proteins in the amygdala (A) and frontal cortex (B) of cognitively normal controls (Ctrl, n = 27, n = 26 amygdala and n = 25 frontal cortex), FTLD-TDP (n = 67), AD-TDP (n = 70) and AD no TDP (n = 27). Data are presented as mean ± s.e.m. * P < 0.05 and **** P < 0.0001, ns: not significant. (C, D) Area under the receiver operating characteristic curves (AUC) showing the discriminatory capability of HDGFL2-CE in the amygdala or frontal cortex to distinguish FTLD-TDP from Ctrl (pink), AD-TDP from Ctrl (gold), and AD-TDP from AD no TDP (black). AUC values are shown. (E–G) Scatterplots of HDGFL2-CE protein and RNA abundance with pTDP-43 abundance in the amygdala (E) and frontal cortex (F) of FTLD-TDP patients, as well as in the amygdala of AD-TDP patients (G). Regression coefficients (β) and P values from linear regression analysis of pTDP-43 with HDGFL2-CE protein and RNA adjusting for age and sex are shown
See this image and copyright information in PMC

References

    1. Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015;349:650–5. 10.1126/science.aab0983 - DOI - PMC - PubMed
    1. Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Bampton A, Lee FCY, Masino L, Qi YA, et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature. 2022;603:131–7. 10.1038/s41586-022-04436-3 - DOI - PMC - PubMed
    1. Ma XR, Prudencio M, Koike Y, Vatsavayai SC, Kim G, Harbinski F, Briner A, Rodriguez CM, Guo C, Akiyama T, et al. TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature. 2022;603:124–30. 10.1038/s41586-022-04424-7 - DOI - PMC - PubMed
    1. Melamed Z, Lopez-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, Freyermuth F, McMahon MA, Beccari MS, Artates JW, et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci. 2019;22:180–90. 10.1038/s41593-018-0293-z - DOI - PMC - PubMed
    1. Klim JR, Williams LA, Limone F, Guerra San Juan I, Davis-Dusenbery BN, Mordes DA, Burberry A, Steinbaugh MJ, Gamage KK, Kirchner R, et al. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci. 2019;22:167–79. 10.1038/s41593-018-0300-4 - DOI - PMC - PubMed

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