Skip to main content

Advertisement

SpringerLink
Log in

ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Mutations in coiled-coil-helix–coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10S55L mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K et al (2014) A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137:2329–2345. https://doi.org/10.1093/brain/awu138

    Article  PubMed  PubMed Central  Google Scholar 

  2. BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO, Acevedo MR et al (2017) FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab 25(935–944):e934. https://doi.org/10.1016/j.cmet.2017.03.005

    Article  CAS  Google Scholar 

  3. Brockmann SJ, Freischmidt A, Oeckl P, Muller K, Ponna SK, Helferich AM et al (2018) CHCHD10 mutations p. R15L and p.G66 V cause motoneuron disease by haploinsufficiency. Hum Mol Genet 27:706–715. https://doi.org/10.1093/hmg/ddx436

    Article  CAS  PubMed  Google Scholar 

  4. Burstein SR, Valsecchi F, Kawamata H, Bourens M, Zeng R, Zuberi A et al (2018) In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. Hum Mol Genet 27:160–177. https://doi.org/10.1093/hmg/ddx397

    Article  CAS  PubMed  Google Scholar 

  5. Cavallaro G (2010) Genome-wide analysis of eukaryotic twin CX9C proteins. Mol BioSyst 6:2459–2470. https://doi.org/10.1039/c0mb00058b

    Article  CAS  PubMed  Google Scholar 

  6. Crawley JN (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835:18–26

    Article  CAS  PubMed  Google Scholar 

  7. Custer SK, Neumann M, Lu H, Wright AC, Taylor JP (2010) Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet 19:1741–1755. https://doi.org/10.1093/hmg/ddq050ddq050

    Article  CAS  PubMed  Google Scholar 

  8. DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668

    Article  CAS  PubMed  Google Scholar 

  9. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240

    Article  PubMed  Google Scholar 

  10. Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS et al (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 24:9434–9440. https://doi.org/10.1523/JNEUROSCI.3080-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fratter CDE, Carver J, Sergeant K, Barbosa IA, Hofer M, Esiri M et al (2017) Mitochondrial disease and lipid storage myopathy due to mutation in CHCHD10 or DNM1L and disordered mitochondrial dynamics. Neuromusc Disord 27S1:S21

    Article  Google Scholar 

  12. Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A (2003) ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 31:3784–3788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M et al (2016) CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med 8:58–72. https://doi.org/10.15252/emmm.201505496

    Article  CAS  PubMed  Google Scholar 

  14. Gostimskaya I, Galkin A (2010) Preparation of highly coupled rat heart mitochondria. J Vis Exp. https://doi.org/10.3791/2202

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huang X, Wu BP, Nguyen D, Liu YT, Marani M, Hench J et al (2018) CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10. Hum Mol Genet. https://doi.org/10.1093/hmg/ddy270

    Article  PubMed  PubMed Central  Google Scholar 

  16. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A et al (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524–1528. https://doi.org/10.1126/science.1244360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kawamata H, Manfredi G (2017) Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. J Cell Biol 216:3917–3929. https://doi.org/10.1083/jcb.201709172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khan NA, Nikkanen J, Yatsuga S, Jackson C, Wang L, Pradhan S et al (2017) mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab 26(419–428):e415. https://doi.org/10.1016/j.cmet.2017.07.007

    Article  CAS  Google Scholar 

  19. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36. https://doi.org/10.1186/gb-2013-14-4-r36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P et al (2013) Object recognition test in mice. Nat Protoc 8:2531–2537. https://doi.org/10.1038/nprot.2013.155

    Article  CAS  PubMed  Google Scholar 

  21. Lehmer C, Schludi MH, Ransom L, Greiling J, Junghanel M, Exner N et al (2018) A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS. EMBO Mol Med. https://doi.org/10.15252/emmm.201708558

    Article  PubMed  PubMed Central  Google Scholar 

  22. Li YR, King OD, Shorter J, Gitler AD (2013) Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201:361–372. https://doi.org/10.1083/jcb.201302044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. https://doi.org/10.1016/j.neuron.2013.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Martineau E, Di Polo A, Vande Velde C, Robitaille R (2018) Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS. Elife. https://doi.org/10.7554/elife.41973

    Article  PubMed  PubMed Central  Google Scholar 

  26. Melber A, Haynes CM (2018) UPR(mt) regulation and output: a stress response mediated by mitochondrial–nuclear communication. Cell Res 28:281–295. https://doi.org/10.1038/cr.2018.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Milner TA, Waters EM, Robinson DC, Pierce JP (2011) Degenerating processes identified by electron microscopic immunocytochemical methods. Methods Mol Biol 793:23–59. https://doi.org/10.1007/978-1-61779-328-8_3

    Article  CAS  PubMed  Google Scholar 

  28. Palomo GM, Granatiero V, Kawamata H, Konrad C, Kim M, Arreguin AJ et al (2018) Parkin is a disease modifier in the mutant SOD1 mouse model of ALS. EMBO Mol Med. https://doi.org/10.15252/emmm.201808888

    Article  PubMed  PubMed Central  Google Scholar 

  29. Perrone F, Nguyen HP, Van Mossevelde S, Moisse M, Sieben A, Santens P et al (2017) Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients. Neurobiol Aging 51:177.e9–177.e16. https://doi.org/10.1016/j.neurobiolaging.2016.12.008

    Article  CAS  Google Scholar 

  30. Purandare N, Somayajulu M, Huttemann M, Grossman LI, Aras S (2018) The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J Biol Chem 293:6517–6529. https://doi.org/10.1074/jbc.RA117.001073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Purice MD, Taylor JP (2018) Linking hnRNP function to ALS and FTD pathology. Front Neurosci 12:326. https://doi.org/10.3389/fnins.2018.00326

    Article  PubMed  PubMed Central  Google Scholar 

  32. Quiros PM, Prado MA, Zamboni N, D’Amico D, Williams RW, Finley D et al (2017) Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol 216:2027–2045. https://doi.org/10.1083/jcb.201702058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sfakianos AP, Mellor LE, Pang YF, Kritsiligkou P, Needs H, Abou-Hamdan H et al (2018) The mTOR-S6 kinase pathway promotes stress granule assembly. Cell Death Differ 25:1766–1780. https://doi.org/10.1038/s41418-018-0076-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Siegmund SE, Yang H, Sharma R, Javors M, Skinner O, Mootha V et al (2017) Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. Hum Mol Genet 26:4588–4605. https://doi.org/10.1093/hmg/ddx341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Straub IR, Janer A, Weraarpachai W, Zinman L, Robertson J, Rogaeva E et al (2018) Loss of CHCHD10-CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS. Hum Mol Genet 27:178–189. https://doi.org/10.1093/hmg/ddx393

    Article  CAS  PubMed  Google Scholar 

  36. Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M et al (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10:806–818. https://doi.org/10.1016/S1474-4422(11)70155-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L (2013) Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol 31:46–53. https://doi.org/10.1038/nbt.2450

    Article  CAS  PubMed  Google Scholar 

  38. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ et al (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515. https://doi.org/10.1038/nbt.1621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Woo JA, Liu T, Trotter C, Fang CC, De Narvaez E, LePochat P et al (2017) Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nat Commun 8:15558. https://doi.org/10.1038/ncomms15558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge the funding support of Muscular Dystrophy Association Grant MDA382033 (to G. M.) for this project. We also acknowledge The Jackson Laboratory Genome Engineering Technology and Physiology cores. Costs were defrayed by Cancer Center Support, National Cancer Institute (Grant CA034196) to The Jackson Laboratory. Additional studies were supported using Grant NIH Precision Genetics U54 OD020351 (to C. L.) and NIH/NINDS R01NS062055 (to G. M.). We also acknowledge the WCMC’s Center of Comparative Medicine and Pathology, the Neuroanatomy EM Core in the BMRI, and the EM Imaging Core of WCM.

Author information

Authors and Affiliations

  1. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA

    Corey J. Anderson, Kirsten Bredvik, Suzanne R. Burstein, Samantha M. Meadows, Jalia Dash, Teresa A. Milner, Hibiki Kawamata & Giovanni Manfredi

  2. The Rare and Orphan Disease Center, JAX Center for Precision Genetics, 600 Main Street, Bar Harbor, ME, 04609, USA

    Crystal Davis, Laure Case, Aamir Zuberi & Cathleen Lutz

  3. Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Ave, New York, NY, 10065, USA

    Samantha M. Meadows

  4. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA

    Teresa A. Milner

  5. Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY, 10065, USA

    Alessandra Piersigilli

Authors
  1. Corey J. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kirsten Bredvik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzanne R. Burstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Crystal Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samantha M. Meadows
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jalia Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laure Case
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Teresa A. Milner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hibiki Kawamata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aamir Zuberi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alessandra Piersigilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cathleen Lutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Giovanni Manfredi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GM and CL conceived the study. GM, CL, CJA, AP, TAM, HK, and SRB contributed to experimental design. CL, AZ, CD, and LC designed and performed gene editing and mouse phenotyping. CJA, KB, and SRB performed behavioral experiments. CD and LC performed echocardiography experiments. CJA, TAM, AP, and KB performed histology and electron microscopy experiments. CJA, KB, HK, JD, and SM performed immunohistochemistry and biochemical experiments. GM and CJA analyzed data and drafted the manuscript with input from other authors.

Corresponding author

Correspondence to Giovanni Manfredi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 3678 kb)

Supplementary material 2 (XLS 9722 kb)

Supplementary material 3 (MP4 14128 kb)

Supplementary material 4 (MP4 18681 kb)

Supplementary material 5 (MP4 2830 kb)

Supplementary material 6 (MP4 4635 kb)

Supplementary material 7 (MP4 1853 kb)

Supplementary material 8 (MP4 1121 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Anderson, C.J., Bredvik, K., Burstein, S.R. et al. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol 138, 103–121 (2019). https://doi.org/10.1007/s00401-019-01989-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-01989-y

Keywords

Search

Navigation