Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology
Éanna B Ryan, Jianhua Yan, Nimrod Miller, Sudarshan Dayanidhi, Yongchao C Ma, Han-Xiang Deng, Teepu Siddique, Éanna B Ryan, Jianhua Yan, Nimrod Miller, Sudarshan Dayanidhi, Yongchao C Ma, Han-Xiang Deng, Teepu Siddique
Abstract
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified in patients suffering from various degenerative diseases including mitochondrial myopathy, spinal muscular atrophy Jokela type, frontotemporal dementia, and/or amyotrophic lateral sclerosis (ALS). The pathogenic mechanism underlying CHCHD10-linked divergent disorders remains largely unknown. Here we show that transgenic mice overexpressing an ALS-linked CHCHD10 p.R15L mutation leads to an abbreviated lifespan compared with CHCHD10-WT transgenic mice. The occurrence and severity of the phenotype correlates to transgene copy number. Central nervous system (CNS), skeletal muscle, and cardiac pathology is apparent in CHCHD10-R15L transgenic mice. Despite the pathology, CHCHD10-R15L transgenic mice perform comparably to control mice in motor behavioral tasks until very close to death. Although paralysis is not observed, these models provide insight into the pleiotropic nature of CHCHD10 and suggest a contribution of CNS, skeletal muscle, and cardiac pathology to CHCHD10 p.R15L-ALS pathogenesis.
Keywords: Molecular Biology; Molecular Physiology; Neuroscience.
Conflict of interest statement
The authors declare no competing interests.
© 2021 The Authors.
Figures
References
- Ajroud-Driss S., Fecto F., Ajroud K., Lalani I., Calvo S.E., Mootha V.K., Deng H.X., Siddique N., Tahmoush A.J., Heiman-Patterson T.D., Siddique T. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. Neurogenetics. 2015;16:1–9.
- An J., Shi J., He Q., Lui K., Liu Y., Huang Y., Sheikh M.S. CHCM1/CHCHD6, novel mitochondrial protein linked to regulation of mitofilin and mitochondrial cristae morphology. J. Biol. Chem. 2012;287:7411–7426.
- Anderson C.J., Bredvik K., Burstein S.R., Davis C., Meadows S.M., Dash J., Case L., Milner T.A., Kawamata H., Zuberi A. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol. 2019;138:103–121.
- Aras S., Bai M., Lee I., Springett R., Huttemann M., Grossman L.I. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51.
- Auranen M., Ylikallio E., Shcherbii M., Paetau A., Kiuru-Enari S., Toppila J.P., Tyynismaa H. CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease. Neurol. Genet. 2015;1:e1.
- Bannwarth S., Ait-El-Mkadem S., Chaussenot A., Genin E.C., Lacas-Gervais S., Fragaki K., Berg-Alonso L., Kageyama Y., Serre V., Moore D.G. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329–2345.
- Borel F., Gernoux G., Cardozo B., Metterville J.P., Toro Cabrera G.C., Song L., Su Q., Gao G.P., Elmallah M.K., Brown R.H., Jr., Mueller C. Therapeutic rAAVrh10 mediated SOD1 silencing in adult SOD1(G93A) mice and nonhuman primates. Hum. Gene Ther. 2016;27:19–31.
- Brockmann S.J., Freischmidt A., Oeckl P., Muller K., Ponna S.K., Helferich A.M., Paone C., Reinders J., Kojer K., Orth M. CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. Hum. Mol. Genet. 2018;27:706–715.
- Brown R.H., Al-Chalabi A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 2017;377:162–172.
- Burstein S.R., Valsecchi F., Kawamata H., Bourens M., Zeng R., Zuberi A., Milner T.A., Cloonan S.M., Lutz C., Barrientos A., Manfredi G. In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. Hum. Mol. Genet. 2018;27:160–177.
- Dal Canto M.C., Gurney M.E. A low expressor line of transgenic mice carrying a mutant human Cu,Zn superoxide dismutase (SOD1) gene develops pathological changes that most closely resemble those in human amyotrophic lateral sclerosis. Acta Neuropathol. 1997;93:537–550.
- Darshi M., Trinh K.N., Murphy A.N., Taylor S.S. Targeting and import mechanism of coiled-coil helix coiled-coil helix domain-containing protein 3 (ChChd3) into the mitochondrial intermembrane space. J. Biol. Chem. 2012;287:39480–39491.
- Dejesus-Hernandez M., Mackenzie I.R., Boeve B.F., Boxer A.L., Baker M., Rutherford N.J., Nicholson A.M., Finch N.A., Flynn H., Adamson J. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–256.
- Deng H.X., Bigio E.H., Zhai H., Fecto F., Ajroud K., Shi Y., Yan J., Mishra M., Ajroud-Driss S., Heller S. Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch. Neurol. 2011;68:1057–1061.
- Deng H.X., Zhai H., Bigio E.H., Yan J., Fecto F., Ajroud K., Mishra M., Ajroud-Driss S., Heller S., Sufit R. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann. Neurol. 2010;67:739–748.
- Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., Shi Y., Siddique N., Arrat H. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 2011;68:1440–1446.
- Fischer M., Riemer J. The mitochondrial disulfide relay system: roles in oxidative protein folding and beyond. Int. J. Cell Biol. 2013;2013:742923.
- Funayama M., Ohe K., Amo T., Furuya N., Yamaguchi J., Saiki S., Li Y., Ogaki K., Ando M., Yoshino H. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14:274–282.
- Genin E.C., Madji Hounoum B., Bannwarth S., Fragaki K., Lacas-Gervais S., Mauri-Crouzet A., Lespinasse F., Neveu J., Ropert B., Auge G. Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse. Acta Neuropathol. 2019;138:123–145.
- Genin E.C., Plutino M., Bannwarth S., Villa E., Cisneros-Barroso E., Roy M., Ortega-Vila B., Fragaki K., Lespinasse F., Pinero-Martos E. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol. Med. 2016;8:58–72.
- Heier C.R., Satta R., Lutz C., Didonato C.J. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum. Mol. Genet. 2010;19:3906–3918.
- Herrmann J.M., Riemer J. Mitochondrial disulfide relay: redox-regulated protein import into the intermembrane space. J. Biol. Chem. 2012;287:4426–4433.
- Huang X., Wu B.P., Nguyen D., Liu Y.T., Marani M., Hench J., Benit P., Kozjak-Pavlovic V., Rustin P., Frank S., Narendra D.P. CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10. Hum. Mol. Genet. 2018;27:3881–3900.
- Jaarsma D., Haasdijk E.D., Grashorn J.A., Hawkins R., Van Duijn W., Verspaget H.W., London J., Holstege J.C. Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol. Dis. 2000;7:623–643.
- Jaarsma D., Rognoni F., Van Duijn W., Verspaget H.W., Haasdijk E.D., Holstege J.C. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 2001;102:293–305.
- Jiao B., Xiao T., Hou L., Gu X., Zhou Y., Zhou L., Tang B., Xu J., Shen L. High prevalence of CHCHD10 mutation in patients with frontotemporal dementia from China. Brain. 2016;139:e21.
- Johnson J.O., Glynn S.M., Gibbs J.R., Nalls M.A., Sabatelli M., Restagno G., Drory V.E., Chio A., Rogaeva E., Traynor B.J. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain. 2014;137:e311.
- Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M., Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68:857–864.
- Keith J.L., Swinkin E., Gao A., Alminawi S., Zhang M., Mcgoldrick P., Mckeever P., Robertson J., Rogaeva E., Zinman L. Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis. Neurol. Genet. 2020;6:e394.
- Kim H.J., Kim N.C., Wang Y.D., Scarborough E.A., Moore J., Diaz Z., Maclea K.S., Freibaum B., Li S., Molliex A. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–473.
- Kurzwelly D., Kruger S., Biskup S., Heneka M.T. A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain. 2015;138:e376.
- Kwiatkowski T.J., Bosco D.A., Leclerc A.L., Tamrazian E., Vanderburg C.R., Russ C., Davis A., Gilchrist J., Kasarskis E.J., Munsat T. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323:1205–1208.
- Lehmer C., Schludi M.H., Ransom L., Greiling J., Junghanel M., Exner N., Riemenschneider H., Van Der Zee J., Van Broeckhoven C., Weydt P. A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS. EMBO Mol. Med. 2018;10:e8558.
- Liu T., Woo J.A., Bukhari M.Z., Lepochat P., Chacko A., Selenica M.B., Yan Y., Kotsiviras P., Buosi S.C., Zhao X., Kang D.E. CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia. FASEB J. 2020;34:8493–8509.
- Liu Y.T., Huang X., Nguyen D., Shammas M.K., Wu B.P., Dombi E., Springer D.A., Poulton J., Sekine S., Narendra D.P. Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations. Hum. Mol. Genet. 2020;29:1547–1567.
- Mackenzie I.R., Bigio E.H., Ince P.G., Geser F., Neumann M., Cairns N.J., Kwong L.K., Forman M.S., Ravits J., Stewart H. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol. 2007;61:427–434.
- Mccampbell A., Cole T., Wegener A.J., Tomassy G.S., Setnicka A., Farley B.J., Schoch K.M., Hoye M.L., Shabsovich M., Sun L. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J. Clin. Invest. 2018;128:3558–3567.
- Meng H., Yamashita C., Shiba-Fukushima K., Inoshita T., Funayama M., Sato S., Hatta T., Natsume T., Umitsu M., Takagi J. Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. Nat. Commun. 2017;8:15500.
- Modjtahedi N., Tokatlidis K., Dessen P., Kroemer G. Mitochondrial proteins containing coiled-coil-helix-coiled-coil-helix (CHCH) domains in health and disease. Trends Biochem. Sci. 2016;41:245–260.
- Muller K., Andersen P.M., Hubers A., Marroquin N., Volk A.E., Danzer K.M., Meitinger T., Ludolph A.C., Strom T.M., Weishaupt J.H. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014;137:e309.
- Ott C., Dorsch E., Fraunholz M., Straub S., Kozjak-Pavlovic V. Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. PLoS One. 2015;10:e0120213.
- Penttila S., Jokela M., Bouquin H., Saukkonen A.M., Toivanen J., Udd B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann. Neurol. 2015;77:163–172.
- Project Mine Als Sequencing Consortium CHCHD10 variants in amyotrophic lateral sclerosis: where is the evidence? Ann. Neurol. 2018;84:110–116.
- Purandare N., Somayajulu M., Huttemann M., Grossman L.I., Aras S. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J. Biol. Chem. 2018;293:6517–6529.
- Renton A.E., Majounie E., Waite A., Simon-Sanchez J., Rollinson S., Gibbs J.R., Schymick J.C., Laaksovirta H., Van Swieten J.C., Myllykangas L. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–268.
- Riemer J., Fischer M., Herrmann J.M. Oxidation-driven protein import into mitochondria: insights and blind spots. Biochim. Biophys. Acta. 2011;1808:981–989.
- Rosen D.R., Siddique T., Patterson D., Figlewicz D.A., Sapp P., Hentati A., Donaldson D., Goto J., Oregan J.P., Deng H.X. Mutations in Cu/Zn superoxide-dismutase gene are associated with familial amyotrophic-lateral-sclerosis. Nature. 1993;362:59–62.
- Rosenbohm A., Schmid B., Buckert D., Rottbauer W., Kassubek J., Ludolph A.C., Bernhardt P. Cardiac findings in amyotrophic lateral sclerosis: a magnetic resonance imaging study. Front. Neurol. 2017;8:479.
- Seibenhener M.L., Wooten M.C. Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J. Vis. Exp. 2015:e52434.
- Shababi M., Habibi J., Yang H.T., Vale S.M., Sewell W.A., Lorson C.L. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum. Mol. Genet. 2010;19:4059–4071.
- Simon P., Dupuis R., Costentin J. Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav. Brain Res. 1994;61:59–64.
- Straub I.R., Janer A., Weraarpachai W., Zinman L., Robertson J., Rogaeva E., Shoubridge E.A. Loss of CHCHD10-CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS. Hum. Mol. Genet. 2018;27:178–189.
- Tan C.F., Eguchi H., Tagawa A., Onodera O., Iwasaki T., Tsujino A., Nishizawa M., Kakita A., Takahashi H. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 2007;113:535–542.
- Tu P.H., Raju P., Robinson K.A., Gurney M.E., Trojanowski J.Q., Lee V.M. Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc. Natl. Acad. Sci. U S A. 1996;93:3155–3160.
- Vance C., Rogelj B., Hortobagyi T., De Vos K.J., Nishimura A.L., Sreedharan J., Hu X., Smith B., Ruddy D., Wright P. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–1211.
- Vatsavayai S.C., Yoon S.J., Gardner R.C., Gendron T.F., Vargas J.N., Trujillo A., Pribadi M., Phillips J.J., Gaus S.E., Hixson J.D. Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain. 2016;139:3202–3216.
- Watts G.D., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D., Pestronk A., Whyte M.P., Kimonis V.E. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 2004;36:377–381.
- Wong P.C., Pardo C.A., Borchelt D.R., Lee M.K., Copeland N.G., Jenkins N.A., Sisodia S.S., Cleveland D.W., Price D.L. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14:1105–1116.
- Woo J.A., Liu T., Trotter C., Fang C.C., De Narvaez E., Lepochat P., Maslar D., Bukhari A., Zhao X., Deonarine A. Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nat. Commun. 2017;8:15558.
- Xiao Y., Zhang J., Shu X., Bai L., Xu W., Wang A., Chen A., Tu W.-Y., Wang J., Zhang K. Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment. Hum. Mol. Genet. 2019;29:1784–1796.
- Zhang M., Xi Z., Zinman L., Bruni A.C., Maletta R.G., Curcio S.A., Rainero I., Rubino E., Pinessi L., Nacmias B. Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain. 2015;138:e380.
Source: PubMed