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

Acta Neuropathologica Communications
Arnaud JacquierPhilippe Latour

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 trig...Continue Reading

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Citations

May 15, 2020·Brain : a Journal of Neurology·Arie R GafsonPaul M Matthews
Jul 15, 2020·Cells·Christine E HellwegAgapios Sachinidis
May 30, 2019·Frontiers in Neurology·Udaya Geetha VijayakumarStephanie Marie-Rose Duguez
Sep 29, 2019·Journal of Neuromuscular Diseases·Danique BeijerVincent Timmerman
Aug 12, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Junqiang YanJiarui Huang
Oct 20, 2020·Frontiers in Molecular Neuroscience·Laurent GuillaudMarco Terenzio
May 15, 2021·Journal of the Peripheral Nervous System : JPNS·Francesco ArutaStefano Tozza
Jul 19, 2021·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Andriana CharalampopoulouElisabeth Chroni

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transfections
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