THESIS
2021
1 online resource (x, 119 pages) : illustrations (some color)
Abstract
Neurodegenerative diseases have become one of the major challenges in public health. More people
suffer from neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and
Huntington’s disease (HD). As these diseases progress, patients have severe symptoms including
dementia, memory and learning deficits, cognitive dysfunction, and mental disorders. HD is an
autosomal dominant neurodegenerative disease. HD patients suffer from progressive motor
dysfunction, cognitive defects and neuropsychiatric dysfunctions, and eventually death. It was
revealed that HD is caused by the abnormal expansion of the cytosine-adenine-guanine (CAG)
repeat in the huntingtin gene. Many researchers have focused on uncovering the pathogenic
mechanisms of HD. However, the detailed mechanisms o...[
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Neurodegenerative diseases have become one of the major challenges in public health. More people
suffer from neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and
Huntington’s disease (HD). As these diseases progress, patients have severe symptoms including
dementia, memory and learning deficits, cognitive dysfunction, and mental disorders. HD is an
autosomal dominant neurodegenerative disease. HD patients suffer from progressive motor
dysfunction, cognitive defects and neuropsychiatric dysfunctions, and eventually death. It was
revealed that HD is caused by the abnormal expansion of the cytosine-adenine-guanine (CAG)
repeat in the huntingtin gene. Many researchers have focused on uncovering the pathogenic
mechanisms of HD. However, the detailed mechanisms of neurodegeneration in HD remain
elusive. In particular, how synaptic transmission is altered in the early stage of HD is not clearly
understood yet. Here, I investigated synaptic vesicles release during electrical stimulation in
single presynaptic terminals level in cultured cortical neurons of a zQ175KI HD mouse model
(zQ175) and found that the release of synaptic vesicles is altered during stimulation in HD
cortical neurons. Furthermore, the Ca
2+ influx during electrical stimulation significantly
increased during stimulation in cultured neurons of HD mice. Intriguingly, this increase was
prevented by treating with either BAPTA-AM or ω-conotoxin GVIA (N-type VGCC blocker),
suggesting the involvement of N-type voltage-gated Ca
2+ channels in HD. To further study
altered dynamics and exocytosis of synaptic vesicles, I also performed real-time 3D tracking of
single synaptic vesicle in cultured cortical neurons of zQ175 mice. I found abnormal mobility
and altered vesicle pools of releasing synaptic vesicles. Overexpressing Rab11 or constitutive
active form of Rab11 (EGFP-Rab11AQ70L) rescued the abnormal dynamics and vesicle pools
of synaptic vesicles. Taken together, my work provides new insight into synaptic transmission
in the early stage of HD and shed new light into a possible therapeutic target for HD.
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