Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH.
Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation.
Cell. 2008 Jan 11;132(1):137-48.
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We know, based on Mandelkow’s and Hirokawa’s work, that accumulation of tau in neurons inhibits axonal transport, and may affect synaptic function. Hyperphosphorylation of tau detaches tau from microtubules, and restores axonal transport. However, subsequent formation of neurofibrillary tangles (NFTs) may also affect synaptic function, leading to neuronal dysfunction in disease. Therefore, tau is thought to have a dual role in synapse dysfunction. Sheng’s paper makes us reconsider the mode of mitochondrial axonal transport. Depletion of syntaphilin liberated mitochondria to a mobile state, and affected short-term facilitation in synapses, which means that detaching tau from microtubules by phosphorylation may affect synapse function by altering the mobile state of mitochondria. Indeed, in our recent manuscript, when tau was hyperphosphorylated with age in mice expressing human tau, the animals showed an impairment of spatial memory accompanied by synapse loss in the entorhinal cortex. If the state of tau alters the interplay between mitochondria and syntaphilin, the mobile state of mitochondria may be a cause of memory impairment in these aged mice.
The present paper makes an important contribution to understanding the proteins which are responsible for docking of axonal mitochondria and for controlling their mobility. The authors have identified a role for axon-targeted syntaphilin in mitochondrial docking through its interaction with microtubules. When they overexpressed syntaphilin, they report that axonal mitochondria lose mobility. They carried out elegant experiments in which they deleted the mouse syntaphilin gene. This resulted in a higher proportion of axonal mitochondria in the mobile state and reduced the density of mitochondria in axons. Electrophysiologically, the mutant neurons exhibited enhanced short-term facilitation during prolonged stimulation. This appears to be due to an effect on calcium signaling at the presynaptic boutons. They were able to rescue the phenotype by reintroducing the syntaphilin gene into the mutant neurons.
These are important findings in an area that is receiving increasing attention. It is likely that mitochondrial mobility and distribution may be important in neurodegenerative diseases. Impaired axonal transport of mitochondria has been identified in almost all major neurodegenerative diseases including Huntington disease (HD), Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS). In addition, almost all neurodegenerative diseases tend to have degeneration of the distal synapses. This is true in all the major diseases such as AD, Parkinson disease, HD, and ALS. This may be a consequence of impaired axonal transport. The ability to test this by utilizing the knockout mice could prove to be extremely valuable. There are two major possibilities. Increasing axonal transport of mitochondria could be beneficial, since it may allow damaged mitochondria to return to the nucleus where they may be repaired or autophagocytosed. On the other hand, it might lead to fewer mitochondria in the distal synapse, which could further impair distal synaptic function. These will be interesting areas for further investigation.
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