Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death
| Autor: | Valérie Castellani, Edwige Belotti, Alexander J. Abrams, Laurent Schaeffer, Claude Alain Maurage, Tanya Stojkovic, Arnaud Jacquier, Philippe Latour, Guilhem Solé, Cécile Delorme, Marianne Giroux, Odile Dubourg, Adriana P. Rebelo, Stephan Züchner, Raoul Juntas-Morales |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Mutant Apoptosis Caspase 3 Chick Embryo Biology medicine.disease_cause Protein Aggregation Pathological lcsh:RC346-429 Pathology and Forensic Medicine Mice Young Adult 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Charcot-Marie-Tooth Disease Neurofilament Proteins Cell Line Tumor medicine Animals Humans Family Amyotrophic lateral sclerosis Gene lcsh:Neurology. Diseases of the nervous system Aged Neurons Genetics Mutation Research Translation (biology) Middle Aged Spinal cord medicine.disease 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Aggresome Spinal Cord Female Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Communications, Vol 5, Iss 1, Pp 1-15 (2017) Acta Neuropathologica Communications |
| ISSN: | 2051-5960 |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0457-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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