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Organellar Cytoskeletal Disease-Charcot-Marie-Tooth Disease Type 2A (CMT2A)
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Organellar Cytoskeletal Disease - Charcot-Marie-Tooth Disease Type 2A (CMT2A)
Cellular organelles and the cytoskeleton malfunctioning can severely affect human
beings. This paper discusses mitochondrial dysfunction related to Charcot-Marie-Tooth disease
type 2A (CMT2A). It gives a molecular and cellular description of CMT2A, presents its clinical
features, and suggests some methods for using animal models to research the disease.
Molecular and Cellular Characterization
The Mitofusin 2 (MFN2) gene is responsible for the hereditary peripheral neuropathy
identified as Charcot-Marie-Tooth disease type 2A (CMT2A) (Bernard-Marissal et al., 2019).
For their function and distribution within cells, mitochondria often divide and fuse. It is located
at the outer mitochondrial membrane. MFN2 promotes membrane fusion, ensuring proper
mitochondrial networking and bioenergetics (Larrea et al., 2019). Mutations in MFN2 result in
fragmented, nonfunctional mitochondria since they block the process of mitochondrial fusion
from taking place. This disturbance interferes with mitochondrial transport along axons,
especially those at long peripheral neurons, resulting in energy loss and axonal degeneration. An
impaired mitochondrial function also leads to increased oxidative stress, intensifying neuronal
damage that contributes to CMT2A progression (Franco et al., 2022).
Clinical Features
Gradually, distal muscles in the lower and upper limbs become weak and atrophied,
usually during the first or second decade of life. Patients often complain about difficulties while
walking, frequent falling, high-arched feet (pes cavus), and curled toes (hammer toes) (Franco et
al., 2022). Sensory loss starts as the disease progresses, with vibration perception most severely
affected, followed by joint position sense. Reflexes are likely to be reduced or absent in affected
individuals (Bernard-Marissal et al., 2019). Some CMT2A patients also have ocular atrophy,
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hearing loss, and paralysis of vocal cords, which imply that other cranial nerves are involved
alongside motor-sensory neuropathy. The intensity and course of symptoms can differ widely
between individuals, even within the same family (Dorn II, 2020).
Animal Models
Several animal models have been developed to investigate CMT2A, including transgenic
and knockout mice models. MFN2 knockout mouse is among them. MFN2 homozygous deletion
are embryonically fatal, proving the critical role of MFN2 in development (Dorn II, 2020).
Commonly, CMT2A research uses MFN2 heterozygous knockout mice. Poor mitochondrial
transport, axonal degeneration, and mitochondrial fragmentation in these mice closely resemble
the human disease phenotype (Bernard-Marissal et al., 2019). Another useful model is the
Mfn2R94Q transgenic mouse that carries a typical human disease-causing mutation. These mice
progress to motor deficits, axonal degeneration, and mitochondrial dysfunction, which help
explain the causes of disease and identify possible therapeutics (Franco et al., 2022). Moreover,
these models are not only used to replicate various phenotypes of diseases. In preclinical tests of
potential drugs, for instance, they have been demonstrated to be highly relevant. On the other
hand, there is some recent research in this regard showing that drug targeting mitochondrial
dynamics and bioenergetics would work, and an alternative therapeutic approach could be
considered after targeting the same (Dang et al., 2022). Furthermore, they allow for assessing
how gene therapy treatments can fix genetic deficiencies at their root cause to monitor disease
progression over time. Henceforth, we have learned from these animal investigations about how
effective CMT2A drugs can be in improving the quality of life of those affected (Dang et al.,
2022).
Conclusion
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Charcot-Marie-Tooth disease type 2A includes severe neuropathy deficit, which is said to
be a result of a mutation on the MFN2 gene, which affects mitochondria and axons.
Mitochondria also possess their own DNA and a genome that is smaller than that of a bacterium,
which divide and fuse for their function and distribution into cells. It is associated with the outer
mitochondrial membrane MFN2, which is involved in the process of membrane fusion, hence
correct network and bioenergy formation. Various animal models have a real value in enhancing
comprehension of the molecular roles of CMT2A and cellular functions other than being
valuable in assessing different therapies. Therefore, in subsequent research, it is imperative to
create better animal models alongside the identification of novel treatment approaches to
alleviate society's load.
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References
Bernard-Marissal, N., van Hameren, G., Juneja, M., Pellegrino, C., Louhivuori, L., Bartesaghi,
L., ... & Chrast, R. (2019). The altered interplay between the endoplasmic reticulum and
mitochondria in Charcot–Marie–Tooth type 2A neuropathy. Proceedings of the National
Academy of Sciences, 116(6), 2328-2337. https://doi.org/10.1073/pnas.1810932116
Dang, X., Walton, E. K., Zablocka, B., Baloh, R. H., Shy, M. E., & Dorn, G. W. (2022).
Mitochondrial phenotypes in genetically diverse neurodegenerative diseases and their
response to mitofusin activation. Cells, 11(6), 1053.
https://doi.org/10.3390/cells11061053
Dorn II, G. W. (2020). Mitofusins are mitochondrial anchors and tethers. Journal of molecular
and cellular cardiology, 142, 146-153. https://doi.org/10.1016/j.yjmcc.2020.04.016
Franco, A., Dang, X., Zhang, L., Molinoff, P. B., & Dorn, G. W. (2022). Mitochondrial
dysfunction and pharmacodynamics of mitofusin activation in murine Charcot-Marie-
Tooth disease type 2A. Journal of Pharmacology and Experimental Therapeutics, 383(2),
137–148. DOI: https://doi.org/10.1124/jpet.122.001332
Larrea, D., Pera, M., Gonnelli, A., Quintana–Cabrera, R., Akman, H. O., Guardia-Laguarta,
C., ... & Giacomello, M. (2019). MFN2 mutations in Charcot–MarieTooth disease alter
mitochondria-associated ER membrane function but do not impair bioenergetics. Human
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