Neurodegenerative diseases are characterized by a series of dysfunctions which result from progressive neurodegeneration and severe atrophy in the central nervous system. The mechanisms of these neurodegenerative diseases remain obscure. Huntington's disease (HD) was investigated as a model to better understand the general mechanisms of neurodegeneration. HD is an autosomal dominant inherited neurodegenerative disease caused by expansion of the cytosine-adenine-guanine (CAG) repeat in the mutant huntingtin gene. It results in progressive motor dysfunction, cognitive deficits and other disorders in human patients, which is found associated with irreversible neuron loss in striatum, cortex and other brain regions at different stages.

However, the detailed mechanisms of neurodegeneration...[ Read more ]

Neurodegenerative diseases are characterized by a series of dysfunctions which result from progressive neurodegeneration and severe atrophy in the central nervous system. The mechanisms of these neurodegenerative diseases remain obscure. Huntington's disease (HD) was investigated as a model to better understand the general mechanisms of neurodegeneration. HD is an autosomal dominant inherited neurodegenerative disease caused by expansion of the cytosine-adenine-guanine (CAG) repeat in the mutant huntingtin gene. It results in progressive motor dysfunction, cognitive deficits and other disorders in human patients, which is found associated with irreversible neuron loss in striatum, cortex and other brain regions at different stages.

However, the detailed mechanisms of neurodegeneration in HD are not clearly understood yet. A great interest has been generated since the finding that synaptic dysfunction occurs before neurodegeneration and subsequent neuron loss in HD pathogenesis. Besides, BDNF is widely accepted as one of the promising candidates for therapeutic strategies of neurodegenerative diseases. It is believed that pharmacological interventions which could delay or stop the early neuropathology of HD should inspire further therapeutic strategies for treating different neurodegenerative diseases.

In this work, we report the first real-time measurement of synaptic transmission and BDNF delivery in cultured neurons of zQ175 mice. Compared to wild-type, the cortical neurons of zQ175 mice showed a significant increase in synaptic vesicle release, which was confirmed by the decrease in paired-pulse ratio. Besides, increased Ca²⁺ influx underling the activity-dependent exocytosis was also identified in these cortical neurons. Corticostriatal BDNF delivery is also found impaired at different levels. Not only in pure culture, BDNF release was also found decreased in cortical axon projections co-cultured with striatal neurons from HD mice. The kinetics of single BDNF-containing vesicles was also categorized into different groups. The proportion of full release events was significantly decreased in HD cortical neurons.

This work targeting mechanisms of early neurodegeneration in HD will benefit our understanding towards general mechanisms of neurodegenerative diseases. Besides, these paradigms applied for detailed functional measurements could inspire preclinical evaluation of potential therapeutic targets of different neurodegenerative diseases.