Defects in mitochondrial proteins can cause neuropathies
Published: 07-12-2021 In Case Studie
"Mitochondria are the powerhouse of the cell".
This is the sentence that everyone has heard while learning about these organelles in biology class.
And it is true: within mitochondria takes place the main chemical reaction by which our body obtains energy. This is why they are such important organelles.
The amount of mitochondria needs to be closely controlled to ensure adequate energy production. Two processes are responsible for this: mitochondrial fusion (two mitochondria fusing together into one) and mitochondrial fission (one mitochondrion splitting into two). Both processes together can be called mitochondrial dynamics. A balance between these processes is necessary to keep a healthy population of mitochondria in cells. Since neuronal cells require large amounts of energy and are lengthy, they are particularly sensitive to alterations in these processes. Thus, mitochondrial dynamics is really important in neurons, and in axons (i.e. most elongated part of the neuron) in particular.
The relationship between mitochondrial dynamics and neuropathies
As we have stated, both proteins have an important paper in development.
In fact, mutations in the genes that produce them have been implicated in many neurodegenerative disorders and disorders of the peripheral nerves such as, Charcot-Marie-Tooth disease (CMT), early-onset and progressive dominant optic atrophy or hereditary sensory and autonomic neuropathy. It has also been hypothesized that alterations in these genes can cause small-fiber neuropathy (SFN).
To evaluate the response of the larvae to temperature, the larvae were studied using a ZebraBox system. The plate containing the larvae was placed in the ZebraBox and after 30 minutes in the dark at 28.5°C, the experiment started. They first recorded larval activity for 10 minutes at 28.0°C, after which they increased the water temperature until a maximum of 36.5°C for the GDAP1 mutants and 35.8°C for the OPA1 mutants. ZebraLab software automatically determined the size of the larvae and recorded the movement of the zebrafish to determine their activity (number of pixels that change from one frame to the next). The
Absence of GDAP1 alters pain sensitivity and reduces the number of sensory neurons
With this experiment, the team discovered that wild-type zebrafish (i.e. fish without any mutations, used as a control to compare to) increased their swimming activity as the temperature rose. In GDAP1 mutants this response was very reduced, while in OPA1 mutants the response was similar to wild-type zebrafish .
The discoveries relating GDAP1 with altered pain sensitivity and decreased amount of sensory neurons remind of the symptoms of SFN, thus, possibly indicating a role of the protein in the development of SFN. GDAP1 mutants, present a developmental defect possibly caused by energy deficits as a result of altered mitochondrial distribution.
In conclusion, the study demonstrated that GDAP1, a key protein for mitochondrial fission, has an important role in the development of sensory neurons. Its absence leads to characteristics that remind of SFN in zebrafish . Unexpectedly, however, the absence of OPA1 (responsible for mitochondrial fusion) has none of the effects attributable to GDAP1 absence. The findings demonstrate an impaired development in the absence of GDAP1 but, surprisingly without any defects for mitochondrial fission. The apparent normality of fission mechanisms may be due to a failure to study mitochondria in the developing neurons or because other mechanisms may account for mitochondrial fission.
First steps for the future of neuropathies treatment
Eijkenboom I, Vanoevelen JM, Hoeijmakers JGJ, et al. A zebrafish model to study small-fiber neuropathy reveals a potential role for GDAP1. Mitochondrion. https://doi.org/10.1016/j.mito.2019.01.002
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Tags: #zebrafish, #behavior, #neuroscience