Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models

Perez-Olle, Raul; Jones, S.; Liem, Ronald K.H.

doi:10.1093/hmg/ddh236

Cited by 74 publications

(71 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pathology overlaps with the previously described GAN, which is also classified as a neuronal CMT (72). A number of CMT-associated NEFL mutations have been tested for their ability to self assemble and coassemble with wild-type NFTPs (80). The results showed that all pathogenic mutations disrupted the assembly and transport of neuronal IFs.…”

Section: Neuronal If Inclusion Disease a Recently Described Disease mentioning

confidence: 58%

Dysfunctions of neuronal and glial intermediate filaments in disease

Liem

Messing²

2009

J. Clin. Invest.

125

100

View full text Add to dashboard Cite

Intermediate filaments (IFs) are abundant structures found in most eukaryotic cells, including those in the nervous system. In the CNS, the primary components of neuronal IFs are α-internexin and the neurofilament triplet proteins. In the peripheral nervous system, a fifth neuronal IF protein known as peripherin is also present. IFs in astrocytes are primarily composed of glial fibrillary acidic protein (GFAP), although vimentin is also expressed in immature astrocytes and some mature astrocytes. In this Review, we focus on the IFs of glial cells (primarily GFAP) and neurons as well as their relationship to different neurodegenerative diseases.

show abstract

Section: Neuronal If Inclusion Disease a Recently Described Disease mentioning

confidence: 58%

Dysfunctions of neuronal and glial intermediate filaments in disease

Liem

Messing²

2009

J. Clin. Invest.

125

100

View full text Add to dashboard Cite

show abstract

“…5,6 The mutation carried by our patients that leads to a substitution of glutamic acid to lysine at position 396 (Glu396Lys) occurs in a highly conserved motive at the end of the rod domain, and several families with the same mutation as well as a transgenic mouse model have been reported in literature. [5][6][7]18,19 The axons of the mutant mouse had fewer NFs than those of the wild-type, and accordingly, sural nerve biopsies from patients have shown the presence of axons either devoid of or with a variable density of NFs. Our results from both immunohistochemistry and WB analysis are in keeping with these data, demonstrating reduced levels of NFs in cutaneous nerve fibers.…”

Section: 12mentioning

confidence: 96%

“…4 NEFL mutations are distributed throughout the 3 functional domains of the NF-L (head, rod, and tail) and different mutations have been shown to lead to distinct pathologic effect. 5,6 Previous studies in a transgenic mouse model carrying a Glu396Lys have demonstrated accumulation of NFs in the neuronal cell body, with decreased NFs in axons. 6 Sural nerve biopsies from patients with the Glu396Lys have shown the presence of axons with a variable density of NFs.…”

mentioning

confidence: 99%

Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

et al. 2015

View full text Add to dashboard Cite

Objective: To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E).Methods: A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis. Results:The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and a-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of a-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E.Conclusions: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E. Charcot-Marie-Tooth disease (CMT) is a group of peripheral neuropathies associated with mutations in more than 80 distinct genes. CMT is divided into different forms based on the pattern of inheritance and neurophysiology. Electrophysiologic studies allow for classification of CMT into demyelinating (CMT1) and axonal (CMT2) forms.1 The classification of CMT has been further divided into subtypes, identified by letters, as defined by the mutated gene.2 CMT2E refers to autosomal dominant CMT2 caused by mutations in the neurofilament light chain (NEFL) gene. Some patients with NEFL mutations have slow conduction velocities, in the "demyelinating" range, and are characterized as having CMT1F. Patients with CMT2E and CMT1F are clinically heterogeneous and the age at onset ranges from infancy, typically with severe impairment, to adulthood with milder impairment. Usually those with slowed conductions present early either in infancy with delayed motor milestones or in late childhood/early adolescence.

show abstract

“…Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy affecting motor and sensory nerves of the peripheral nervous system (29). In CMT, disruption of assembly and aggregation of NF-L occur from mutations of NF-L (30,31). Recently, it was reported that CMT mutations of NF-L and small heat-shock protein B1 have similar disruptive effects on the NF network, leading to aggregation of NF-L protein with progressive degeneration and loss of viability of motor neurons (32).…”

Section: Resultsmentioning

confidence: 99%

Salsolinol, a tetrahydroisoquinoline-derived neurotoxin, induces oxidative modification of neurofilament-L: protection by histidyl dipeptides

Kang¹

2012

BMB Reports

View full text Add to dashboard Cite

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a compound derived from dopamine metabolism and is capable of causing dopaminergic neurodegeneration. Oxidative modification of neurofilament proteins has been implicated in the pathogenesis of neurodegenerative disorders. In this study, oxidative modification of neurofilament-L (NF-L) by salsolinol and the inhibitory effects of histidyl dipeptides on NF-L modification were investigated. When NF-L was incubated with 0.5 mM salsolinol, the aggregation of protein was increased in a time-dependent manner. We also found that the generation of hydroxyl radicals (•OH) was linear with respect to the concentrations of salsolinol as a function of incubation time. NF-L exposure to salsolinol produced losses of glutamate, lysine and proline residues. These results suggest that the aggregation of NF-L by salsolinol may be due to oxidative damage resulting from free radicals. Carnosine, histidyl dipeptide, is involved in many cellular defense processes, including free radical detoxification.

show abstract

Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models

Cited by 74 publications

References 48 publications

Dysfunctions of neuronal and glial intermediate filaments in disease

Dysfunctions of neuronal and glial intermediate filaments in disease

Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

Salsolinol, a tetrahydroisoquinoline-derived neurotoxin, induces oxidative modification of neurofilament-L: protection by histidyl dipeptides

Contact Info

Product

Resources

About