Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death

Arnaud Jacquier, Cécile Delorme, Edwige Belotti, Raoul Juntas-Morales, Guilhem Solé, Odile Dubourg, Marianne Giroux, Claude Alain Maurage, Valérie Castellani, Adriana Rebelo, Alexander Abrams, Stephan Züchner, Tanya Stojkovic, Laurent Schaeffer, Philippe Latour

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9 Scopus citations

Abstract

Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.

Original languageEnglish (US)
Number of pages1
JournalActa neuropathologica communications
Volume5
Issue number1
DOIs
StatePublished - Jul 14 2017

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Jacquier, A., Delorme, C., Belotti, E., Juntas-Morales, R., Solé, G., Dubourg, O., Giroux, M., Maurage, C. A., Castellani, V., Rebelo, A., Abrams, A., Züchner, S., Stojkovic, T., Schaeffer, L., & Latour, P. (2017). Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. Acta neuropathologica communications, 5(1). https://doi.org/10.1186/s40478-017-0457-1