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2328.Full.Pdf Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy Nathalie Bernard-Marissala,b,1, Gerben van Hamerenc, Manisha Junejad,e, Christophe Pellegrinof, Lauri Louhivuorig, Luca Bartesaghih,i, Cylia Rochata, Omar El Mansoura, Jean-Jacques Médardh,i, Marie Croisierj, Catherine Maclachlanj, Olivier Poirotk, Per Uhléng, Vincent Timmermand,e, Nicolas Tricaudc, Bernard L. Schneidera,1,2, and Roman Chrasth,i,1,2 aBrain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; bMarseille Medical Genetics, INSERM, Aix-Marseille Univ, 13385 Marseille, France; cINSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34295 Montpellier, France; dPeripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium; eInstitute Born Bunge, 2610 Antwerp, Belgium; fInstitut de Neurobiologie de la Méditerranée, INSERM, Aix-Marseille Univ, 13009 Marseille, France; gDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; hDepartment of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden; iDepartment of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden; jCentre of Interdisciplinary Electron Microscopy, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; and kDepartment of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland Edited by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved December 14, 2018 (received for review June 26, 2018) Mutations in the MFN2 gene encoding Mitofusin 2 lead to the axons (8). However, the long-term progression of the disease and development of Charcot–Marie–Tooth type 2A (CMT2A), a domi- the mechanisms underlying motor and/or sensory dysfunction nant axonal form of peripheral neuropathy. Mitofusin 2 is local- have not been fully characterized in this model. In vitro, primary ized at both the outer membrane of mitochondria and the sensory and motor neurons overexpressing mutated MFN2,or endoplasmic reticulum and is particularly enriched at specialized motoneurons differentiated from CMT2A iPS cells, both display contact regions known as mitochondria-associated membranes mild defects in mitochondrial transport as well as mitochondrial (MAM). We observed that expression of MFN2R94Q induces distal fragmentation (10–12, 14–16). In sensory neurons expressing axonal degeneration in the absence of overt neuronal death. The MFN2R94Q, overexpression of the homologous mitochondrial presence of mutant protein leads to reduction in endoplasmic re- protein MFN1 partially restores mitochondrial fusion and res- ticulum and mitochondria contacts in CMT2A patient-derived fi- cues mitochondrial transport and axonal degeneration (10), broblasts, in primary neurons and in vivo, in motoneurons of a suggesting the existence of additional mechanisms underlying mouse model of CMT2A. These changes are concomitant with en- the MFN2R94Q-related pathophysiology. doplasmic reticulum stress, calcium handling defects, and changes Interestingly, a fraction of MFN2 is also located at the endo- in the geometry and axonal transport of mitochondria. Impor- plasmic reticulum (ER) membrane, in particular at specialized tantly, pharmacological treatments reinforcing endoplasmic retic- sites of contacts with mitochondria called mitochondria-associated – ulum mitochondria cross-talk, or reducing endoplasmic reticulum membranes (MAM) (17). The MAM control several cellular stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular Significance mechanism contributing to CMT2A pathology mediated by mutated MFN2. Interactions between mitochondria and the endoplasmic re- motoneurons | endoplasmic reticulum | mitochondria | CMT2A | ticulum (ER) at the level of mitochondria-associated mem- neuropathy branes (MAM) constitute a key signaling hub, emerging as a shared target altered in multiple neurodegenerative diseases. – – – – We use both in vivo and in vitro models of Charcot Marie harcot Marie Tooth (CMT) disease, also known as heredi- Tooth type 2A, an axonal form of neuropathy, to demonstrate Ctary motor and sensory peripheral neuropathy, represents a that the presence of mutated Mitofusin 2 leads to altered clinically heterogeneous group of inherited neurological disor- MAM. In neurons, these modifications occur concomitantly ders with a prevalence of 1 in 2,500 (1, 2). These diseases result with activation of ER stress response, dysregulated calcium from defects in axons or in myelin or in both. Among the axonal handling, and alterations in mitochondrial morphology and forms of CMT, around 10 to 20% are linked to mutations in the transport, collectively contributing to axonopathy. Impor- MFN2 gene, encoding Mitofusin 2, and are referred to as – tantly, the reported results indicate that the pathological CMT2A (3 5). The symptoms of CMT2A are mainly charac- consequences of mutated Mitofusin 2 may be targeted with terized by progressive distal muscle weakness and atrophy, foot drugs reinforcing the ER–mitochondria cross-talk and/or deformities, areflexia, and sensory loss (6). However, the age of reducing ER stress. disease onset and the severity of symptoms are highly variable among CMT2A patients (6). Author contributions: N.B.-M., O.P., P.U., V.T., N.T., B.L.S., and R.C. designed research; MFN2 is a dynamin-like GTPase protein originally identified N.B.-M., G.v.H., M.J., C.P., L.L., L.B., C.R., O.E.M., J.-J.M., M.C., C.M., and O.P. performed at the outer membrane of mitochondria, where it regulates mi- research; N.B.-M., G.v.H., M.J., C.P., L.L., L.B., O.P., P.U., V.T., N.T., B.L.S., and R.C. analyzed tochondrial fusion (7). Characterization of in vitro and in vivo data; and N.B.-M., B.L.S., and R.C. wrote the paper. models of the disease based on the expression of mutated The authors declare no conflict of interest. MFN2 has led to substantial insights into the CMT2A patho- This article is a PNAS Direct Submission. physiology (8–12). Multiple mouse models have been developed Published under the PNAS license. for CMT2A (8, 13–15); however, a transgenic line overexpressing 1To whom correspondence may be addressed. Email: [email protected], MFN2R94Q specifically in neurons (mitoCharc mice or CMT2A [email protected], or [email protected]. Tg) most closely mimics the late-onset CMT2A pathology (8). 2B.L.S. and R.C. contributed equally to this work. CMT2A Tg mice develop locomotor dysfunction from the age of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 5 mo on, a pathologic effect associated at a late stage of the 1073/pnas.1810932116/-/DCSupplemental. disease with the accumulation of mitochondria in small-caliber Published online January 18, 2019. 2328–2337 | PNAS | February 5, 2019 | vol. 116 | no. 6 www.pnas.org/cgi/doi/10.1073/pnas.1810932116 Downloaded by guest on October 2, 2021 processes such as lipid metabolism, calcium homeostasis, mi- A WT B * 6 months tochondrial dynamics, and autophagy/mitophagy (18, 19). Several 5 CMT2A Tg 300 12 months studies have highlighted the role of MAM in neuronal function, 250 4 [s] with important implications in various neurodegenerative disor- 200 ders (20–25). MFN2 has been proposed to regulate either posi- [g] 3 150 tively or negatively the association between the two organelles (17, 2 26–28). However, it is unknown how CMT2A-associated MFN2 Force 100 1 mutations affect MAM functioning and what the potential Latency to fall 50 consequences for CMT2A pathology are. In addition to MFN2, 0 0 mutations in other mitochondrial proteins including GDAP1, Left paw Rigth paw Left paw Rigth paw WT CMT2A Tg 6 months 12 months OPA1, DNM1L, ATAD3A, and SLC25A46 affect mitochondrial E α-Bungarotoxin SV2A biology and lead to neurological diseases (29, 30). Similarly, mu- C D 8 100 tations in proteins affecting shape and function of ER including * WT [%] 80 CMT2A Tg FAM134B,ATL1,ATL3,andBSCL2arelinkedtodisturbedneu- 6 ronal function (2). These studies indicate the importance of both 60 WT 20μm mitochondrial and ER physiology and interorganelle communi- 4 40 * cation in the field of neuropathy. * 2 In the present study, we characterized in detail the neuropathy 20 R94Q NMJ innervation phenotype caused by expression of MFN2 in both in vitro Motoneuron number 0 0 per ventral horn section WT CMT2A Tg * and in vivo CMT2A disease models. Our data show that over- CMT2A Tg expression of MFN2R94Q affects locomotion and gait in CMT2A InnervatedIntermediate Denervated Tg mice and causes the loss of neuromuscular junctions at a late Fig. 1. CMT2A Tg mice show locomotor defects and muscle denervation but stage of the disease. In primary neurons, MFN2R94Q induces R94Q no detectable motoneuronal death. (A) Evaluation of sensory function with axonal degeneration. At the cellular level, MFN2 expression the von Frey test at the age of 6 and 12 mo (WT: n = 11 and CMT2A Tg: n = leads to the loss of MAM, ER stress, intracellular calcium han- 12). Statistical analysis: two-way repeated-measures ANOVA (group × time) dling defects, and impaired mitochondrial dynamics. Impor- with Newman–Keuls post hoc test. (B) Evaluation of motor function with tantly, we observe that pharmacological treatments to reinforce rotarod test at the age of 6 and 12 mo (WT: n = 11 and CMT2A Tg: n = 12). × MAM function or block ER stress can rescue some of
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