Disease Modeling and Therapeutic Strategies in CMT2A: State of the Art

Abstract

Mitofusin 2 (MFN2) is a protein of the mitochondrial outer membrane that belongs to a family of highly conserved dynamin-related GTPases. It is implicated in several intracellular pathways; however, its main role is the regulation of mitochondrial dynamics, in particular mitochondrial fusion. Mutations in MFN2 are associated with Charcot–Marie–Tooth disease type 2A (CMT2A), a neurological disorder characterized by a wide spectrum of clinical features, primarily a motor sensory neuropathy. The cellular and molecular mechanisms by which MFN2 mutations lead to neuronal degeneration are largely unknown, and there is currently no cure for patients. Here, we present the most recent in vitro and in vivo models of CMT2A and the more promising therapeutic approaches under development. These models and therapies may represent relevant tools for the study and recovery of defective mitochondrial dynamics that seem to play a significant role in the pathogenesis of other more common neurodegenerative diseases.

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Fig. 1

Abbreviations

CMT:

Charcot–Marie–Tooth disease

MCNV:

Motor nerve conduction velocity

MNs:

Motor neurons

SNs:

Sensory neurons

IPSCs:

Induced pluripotent stem cells

ASO:

Antisense oligonucleotide

RNAi:

RNA interference

CRISPR:

Clustered regularly interspersed short palindromic repeats

Cas9:

Caspase 9

KO:

Knockout

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Acknowledgements

We thank Associazione Progetto Mitofusina 2 Onlus and Associazione Amici del Centro Dino Ferrari for their support.

Funding

This study is supported by grant “Ricerca Corrente 2019: Analisi dei pathway molecolari condivisi coinvolti nella patogenesi delle malattie neurodegenerative mediante modelli in vitro basati su cellule staminali” from the Italian Ministry of Health.

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Correspondence to Stefania Corti.

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Barbullushi, K., Abati, E., Rizzo, F. et al. Disease Modeling and Therapeutic Strategies in CMT2A: State of the Art. Mol Neurobiol 56, 6460–6471 (2019). https://doi.org/10.1007/s12035-019-1533-2

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Keywords

  • Mitofusin2
  • Charcot–Marie–Tooth disease type 2
  • Hereditary neuropathies
  • Mitochondrial diseases
  • Molecular therapy
  • Gene therapy
  • Mitofusin agonists