BACKGROUND: Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes. METHODS: A proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins. The candidate proteins were validated through real-time quantitative PCR and western blotting on lymphoblast samples of patients and controls, motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) and sciatic nerves of CMT2 mouse models. RESULTS: Proteomic profiling of patient lymphoblasts resulted in the identification of profilin 2 (PFN2) and guanidinoacetate methyltransferase (GAMT) as commonly downregulated proteins in different genotypes compared with healthy controls. This decrease was also observed at the transcriptional level on screening 43 CMT2 patients and 22 controls, respectively. A progressive decrease in PFN2 expression with age was observed in patients, while in healthy controls its expression increased with age. Reduced PFN2 expression was also observed in motor neurons differentiated from CMT2 patient-derived iPSCs and sciatic nerves of CMT2 mice when compared with controls. However, no change in GAMT levels was observed in motor neurons and CMT2 mouse-derived sciatic nerves. CONCLUSIONS: We unveil PFN2 and GAMT as molecular determinants of CMT2 with possible indications of the role of PFN2 in the pathogenesis and disease progression. This is the first study describing biomarkers that can boost the development of therapeutic strategies targeting a wider spectrum of CMT2 patients.

Aix Marseille University INSERM MMG U1251 Marseille France Brain Mind Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

Brain Mind Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

Department of Clinical Neurological Sciences Centre University Hospital Western University London Ontario Canada

Department of Neuroscience Karolinska Institutet Stockholm Sweden Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

DNA Laboratory Department of Child Neurology 2nd Medical School Charles University and University Hospital Motol Prague Czech Republic

Institute Born Bunge Antwerp Belgium VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium

Institute Born Bunge Antwerp Belgium VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital Antwerpen Belgium

Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK

Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK Leibniz Institut für Analytische Wissenschaften ISAS e 5 Dortmund Germany

Peripheral Neuropathy Research Group University of Antwerp Antwerp Belgium Institute Born Bunge Antwerp Belgium

Stem Cell Institute KU Leuven Leuven Belgium

Unit of Rare Neurodegenerative and Neurometabolic Diseases Department of Clinical Neurosciences C Besta Neurological Institute IRCCS Foundation Milan Italy

VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium

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$a BACKGROUND: Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes. METHODS: A proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins. The candidate proteins were validated through real-time quantitative PCR and western blotting on lymphoblast samples of patients and controls, motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) and sciatic nerves of CMT2 mouse models. RESULTS: Proteomic profiling of patient lymphoblasts resulted in the identification of profilin 2 (PFN2) and guanidinoacetate methyltransferase (GAMT) as commonly downregulated proteins in different genotypes compared with healthy controls. This decrease was also observed at the transcriptional level on screening 43 CMT2 patients and 22 controls, respectively. A progressive decrease in PFN2 expression with age was observed in patients, while in healthy controls its expression increased with age. Reduced PFN2 expression was also observed in motor neurons differentiated from CMT2 patient-derived iPSCs and sciatic nerves of CMT2 mice when compared with controls. However, no change in GAMT levels was observed in motor neurons and CMT2 mouse-derived sciatic nerves. CONCLUSIONS: We unveil PFN2 and GAMT as molecular determinants of CMT2 with possible indications of the role of PFN2 in the pathogenesis and disease progression. This is the first study describing biomarkers that can boost the development of therapeutic strategies targeting a wider spectrum of CMT2 patients.

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$a Azmi, Abdelkrim $u VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.

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$a Baets, Jonathan $u Institute Born Bunge, Antwerp, Belgium. VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.

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$a Roos, Andreas $u Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V., Dortmund, Germany.

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$a Jennings, Matthew J $u Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

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$a Saveri, Paola $u Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.

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$a Bernard-Marissal, Nathalie $u Aix Marseille University, INSERM, MMG, U1251, Marseille, France. Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

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$a Schneider, Bernard L $u Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

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$a Pareyson, Davide $u Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.

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