GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons

Miressi, Federica; Benslimane, Nesrine; Favreau, Fréderic; Rassat, Marion; Richard, Laurence; Bourthoumieu, Sylvie; Laroche, Cécile; Magy, Laurent; Magdelaine, Corinne; Sturtz, Franck; Lia, Anne‐Sophie; Faye, Pierre-Antoine

doi:10.3390/biomedicines9080945

“…In the cellular environment, such a disulfide bond could be formed via a folding catalyst or through changes in the redox environment. The latter has been linked to GDAP1 function [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Sutinen

¹

,

Nguyen

²

,

Raasakka

³

et al. 2022

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in gangliosideinduced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra-and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.Inherited polyneuropathies are a genetically and clinically diverse group of neurodegenerative diseases affecting motor and sensory neurons in the peripheral nervous system (PNS) [1,2]. Mutations in dozens of genes expressed in the PNS cause Charcot-Marie-Tooth disease (CMT). Based on clinical findings, CMT can be classified into three forms: demyelinating, axonal, and intermediate [3,4]. The progress of CMT is linked to the hereditary pattern, whereby the autosomal recessive form has an earlier onset and more severe symptoms than the autosomal dominant form [5][6][7]. Understanding the molecular function of the proteins involved in the etiology of neuropathies is vital in efforts toward treatment and diagnosis.

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“…In the cellular environment, such a disulphide bond could be formed via a folding catalyst or through changes in the redox environment. The latter has been linked to GDAP1 function [75].…”

Section: Discussionmentioning

confidence: 99%

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen

¹

,

Nguyen

²

,

Raasakka

³

et al. 2022

Preprint

1

0

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a large decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices α3, α6, and α7, which is affected by CMT mutations, as well as a hinge in the long helix α6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

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“…In recent studies by Miressi et al, the mutation resulting in p.Ser194* protein truncation was shown to be associated with a low level of protein, probably due to nonsense-mediated RNA decay. This also caused disturbances in the differentiation of motor neurons from hiPSCs [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?

Kabzińska

¹

,

Chabros

²

,

Kamińska

³

et al. 2022

Genes

0

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Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the pathogenic status of p.Glu222Lys in the broader context of the whole exome. We also have analyzed the impact of GDAP1 gene mutations on the morphology of the transfected cells. Despite the use of several tests to determine the pathogenicity of the p.Glu222Lys variant, we cannot point to one that would definitively solve the problem of pathogenicity.

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GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons

Cited by 14 publications

References 52 publications

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?

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