MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives
Giulia Stuppia1, Federica Rizzo1, Giulietta Riboldi1
1Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
Abstract:
Mitofusin 2 (MFN2) is a GTPase dynamin-like protein of the outer mitochondrial membrane, encoded in the nuclear genome by the MFN2 gene located on the short (p) arm of chromosome 1. MFN2 protein is involved in several intracellular pathways, but is mainly involved in a network that has an essential role in several mitochondrial functions, including fusion, axonal transport, interorganellar communication and mitophagy. Mutations in the gene encoding MFN2 are associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a neurological disorder characterized by a wide clinical phenotype that involves the central and peripheral nervous system. Here, we present the clinical, genetic and neuropathological features of human diseases associated with MFN2 mutations. We also report proposed pathogenic mechanisms through which MFN2 mutations likely contribute to the development of neurodegeneration. MFN2-related disorders may occur more frequently than previously considered, and they may represent a paradigm for the study of the defective mitochondrial dynamics that seem to play a significant role in the molecular and cellular pathogenesis of common neurodegenerative diseases; thus they may also lead to the identification of related therapeutic targets.
Insights
Mitofusin 2 (MFN2) protein is crucial for mitochondrial function. Mutations in the MFN2 gene cause Charcot-Marie-Tooth disease type 2A (CMT2A) and may contribute to neurodegeneration.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Mitofusin 2 (MFN2) is a mitochondrial outer membrane protein essential for mitochondrial dynamics, including fusion, axonal transport, and mitophagy.
- MFN2 protein is encoded by the MFN2 gene, mutations of which are linked to Charcot-Marie-Tooth disease type 2A (CMT2A).
Purpose of the Study:
- To present the clinical, genetic, and neuropathological features of MFN2-related human disorders.
- To propose pathogenic mechanisms linking MFN2 mutations to neurodegeneration.
- To highlight MFN2-related disorders as a model for studying mitochondrial dynamics in neurodegenerative diseases and identifying therapeutic targets.
Main Methods:
- Clinical case analysis
- Genetic mutation screening
- Neuropathological examination
- Pathogenic mechanism investigation
Main Results:
- Detailed characterization of the clinical, genetic, and neuropathological profiles of patients with MFN2 mutations.
- Identification of proposed molecular pathways through which MFN2 mutations induce neurodegeneration.
- Evidence suggesting MFN2-related disorders are underdiagnosed and offer insights into common neurodegenerative diseases.
Conclusions:
- MFN2 mutations lead to a spectrum of neurological disorders, including CMT2A, through impaired mitochondrial dynamics.
- MFN2-related disorders serve as a valuable model for understanding neurodegeneration and developing novel therapeutic strategies targeting mitochondrial dysfunction.
