Elucidating the impact of hyperdynamic microtubules on axonal transport 

dysfunction in amyotrophic lateral sclerosis (ALS)

Ting-Jhen Ou (歐庭蓁)1 , Eric Hwang 1,2,3

1 Department of Biological Science & Technology, National Yang Ming Chiao Tung University

2 Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University

3 Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University

Amyotrophic lateral sclerosis (ALS), is a neurodegenerative disease where the motor neurons progressively degenerate, leading to muscle weakness, impaired mobility, paralysis, and ultimately death from respiratory failure within 3 to 5 years. It has been observed that motor neurons in ALS animals exhibit microtubule hyperdynamics (e.g., excessive microtubule growth or shortening). Microtubule stability is crucial for the transportation of organelles, proteins, RNA, and other biomolecules within neurons, especially the longest compartment, axon. Disruption of microtubules can therefore lead to the impairment of function in neurons and the entire nervous system.

The purpose of this study is to understand whether hyperdynamic microtubules lead to the disruptionof axonal transport. Using a specific culturing condition, we can create hyperdynamic microtubules in neurons in vitro. Two bidirectionally transported organelles (mitochondria and lysosomes) will be used to assess the anterograde and retrograde movements in the axon. Live cell imaging of fluorescently labeled mitochondria and lysosomes will be used to observe their movement within the axon. Axonal transport in neurons with hyperdynamic and normal dynamic microtubules will be compared. Because neurons with hyperdynamic microtubules are generated by culturing them in a condition which triggers hyperexcitability (i.e., neurons exhibiting higher frequency and more synchronous electric activity), the inhibitory neurotransmitter GABA will be applied as a control. This will allow us to confirm whether defective axonal transport is caused by microtubule hyperdynamics instead of the specific culturing conditions of neurons.

If hyperdynamic microtubules indeed cause the disruption of axonal transport, future research could focus on regulating microtubule dynamics to address axonal transport defects. Dysregulated microtubule dynamics and defective axonal transport are found in other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Understanding the relationship between these two phenomena can improve our understanding of these debilitating diseases.