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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
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Excess Rab4 rescues synaptic and behavioral dysfunction caused by defective HTT-Rab4 axonal transport in Huntington's
Joseph A White1, Thomas J Krzystek1, Hayley Hoffmar-Glennon1
1Department of Biological Sciences, The State University of New York at Buffalo, New York, 14260, USA.
Acta Neuropathologica Communications
|July 3, 2020
Summary
Huntingtin (HTT) protein moves with Rab4 vesicles in axons, crucial for neuronal transport. In Huntington's disease (HD), this transport is disrupted, causing synaptic and behavioral deficits, suggesting Rab4 as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) involves striatal neuron loss and protein aggregates due to expanded CAG repeats in the huntingtin (HTT) gene.
- HTT is vital for axonal transport, but its specific cargo remains unclear.
Purpose of the Study:
- To identify the cargo of huntingtin (HTT) protein within axonal vesicles.
- To investigate the role of HTT-associated vesicles in Huntington's disease (HD) pathogenesis.
Main Methods:
- In vivo dual-color imaging to track HTT and Rab4 vesicle movement.
- Analysis of vesicle motility using kinesin-1, dynein motors, and HIP1.
- Assessment of behavioral and synaptic defects in HD models and patient-derived neurons.
Main Results:
- HTT colocalizes with Rab4-containing vesicles in axons, forming a unique motile complex.
- Reduced HTT impairs bidirectional Rab4 vesicle motility, leading to axonal and synaptic accumulation.
- Pathogenic HTT disrupts this complex, causing locomotion defects and reduced lifespan, which are rescued by excess Rab4.
- Rab4 motility is also perturbed in human HD patient-derived neurons.
Conclusions:
- A novel HTT-Rab4 vesicle complex involved in axonal transport is identified.
- Disruption of this vesicle's motility in HD contributes to synaptic and behavioral dysfunction.
- Rab4 represents a potential therapeutic target for early intervention in Huntington's disease.
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