Acknowledgements

complex architecture requires the transport and distribution of highly organized organelles,

Aged SLC25A46 mutant mice displayed enhanced hind limb clasping reflex and muscle atrophy, suggesting potential peripheral neuropathy. Acquiring compound muscle action potentials (CMAPs) reduced in mutant sciatic nerve measured by electromyography (EMG) in vivo [39]. Mutant peripheral nerves exhibited sporadic degenerative lesions with local macrophages containing lipid debris and signs of demyelination. In addition, the size of individual endplates in mutant mice was significantly reduced. Retarded neuromuscular junction maturation and improper innervation, early hallmarks of CMT2D, were also documented in mutant muscle

Optical coherence tomography (OCT) scanning on retina for live mice revealed that although the optic discs were grossly normal in terms of retinal appearance, retinas were thinner in aged SLC25A46 mutant mice [39]. Further quantitative measurements indicated that ganglion cell complex (GCC) thicknesses, which includes the nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL), were significantly reduced in adult mutant mice. Retinal and these reductions were associated with retinal ganglion cell loss and atypically small optic nerve axons with reduced neurofilament expression, as well as some axons that exhibited signs of degeneration and demyelination [39, 42]. Pax6+ and GAD65+ GABAergic amacrine cells—both of which form synapses with retinal ganglion cells—were also significantly reduced. These pathological changes are in line with the phenotypic features of ADOA. Ultrastructural studies revealed dysmorphic mitochondria in both the central and peripheral nervous systems. Numerous enlarged and round mitochondria with abnormal cristae were found in Purkinje cell dendrites, while ring- or C-shaped mitochondria were commonly observed in soma. Peripheral nerve axons also had abnormal round, fused, and aggregated

Given the degeneration in long peripheral axons and distal optic nerves of SLC25A46 knockout animal models, the aforementioned findings support the idea that neurons with long axons or complicated dendrites are more sensitive to abnormal mitochondrial dynamics. Similar to the findings in mutant Purkinje cells, this sensitivity could also be due to the impaired transport of hyperfused mitochondria along axons and dendrites, probably due to their abnormal size and/or reduced ATP availability in the distal portions of long axons secondary to mitochondrial dysfunction. Further studies are needed to clarify this point.

SLC25A46 plays a critical role in mitochondrial dynamics and the maintenance of mitochondrial cristae, which are particularly important in neurodevelopment and neurodegeneration. Loss of SLC25A46 function causes a wide spectrum of neurodegenerative diseases, including

[42]. All of these alterations are indicative of peripheral neuropathy.

mitochondria in myelinated and non-myelinated fibers [39, 43].

including mitochondria.

84 Recent Advances in Neurodegeneration

6. Conclusion

This work was supported by the Center for Pediatric Genomics at the Cincinnati Children's Hospital, a grant from the National Institutes of Health (1R01EY026609-01) to Taosheng Huang, and a grant from the National Natural Science Foundation of China (81470299) to Zhuo Li.
