Communication breakdown - synaptic dysfunction in Huntington's disease.

Research output: ThesisDoctoral Thesis (compilation)

Standard

Communication breakdown - synaptic dysfunction in Huntington's disease. / Smith, Ruben.

Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet, 2007.

Research output: ThesisDoctoral Thesis (compilation)

Harvard

APA

Smith, R. (2007). Communication breakdown - synaptic dysfunction in Huntington's disease. Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet.

CBE

Smith R. 2007. Communication breakdown - synaptic dysfunction in Huntington's disease. Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet.

MLA

Smith, Ruben Communication breakdown - synaptic dysfunction in Huntington's disease. Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet. 2007.

Vancouver

Smith R. Communication breakdown - synaptic dysfunction in Huntington's disease.. Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet, 2007.

Author

Smith, Ruben. / Communication breakdown - synaptic dysfunction in Huntington's disease.. Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet, 2007.

RIS

TY - THES

T1 - Communication breakdown - synaptic dysfunction in Huntington's disease.

AU - Smith, Ruben

N1 - Defence details Date: 2007-06-16 Time: 09:15 Place: Segerfalksalen, Wallenberg Neurocentrum, BMC A10, Lund External reviewer(s) Name: Cha, Jang-Ho Title: Associate Professor Affiliation: Harvard, Boston, USA --- <div class="article_info">R Smith, Å Petersen, GP Bates, P Brundin and JY Li. <span class="article_issue_date">2005</span>. <span class="article_title">Depletion of rabphilin 3A in a transgenic mouse model (R6/1) of Huntington's disease, a possible culprit in synaptic dysfunction.</span> <span class="journal_series_title">Neurobiol Dis</span>, <span class="journal_volume">vol 20</span> <span class="journal_pages">pp 673-84</span>.</div> <div class="article_info">R Smith, H Chung, S Rundquist, ML Maat-Schieman, L Colgan, E Englund, YJ Liu, RA Roos, RL Faull, P Brundin and JY Li. <span class="article_issue_date">2006</span>. <span class="article_title">Cholinergic neuronal defect without cell loss in Huntington's disease.</span> <span class="journal_series_title">Hum Mol Genet</span>, <span class="journal_volume">vol 15</span> <span class="journal_pages">pp 3119-31</span>.</div> <div class="article_info">R Smith, P Klein, Y Koc-Schmitz, HJ Waldvogel, RLM Faull, P Brundin, M Plomann and JY Li. <span class="article_issue_date"></span>. <span class="article_title">Loss of SNAP-25 and Rabphilin 3A in sensory-motor cortex in Huntington’s disease.</span> <span class="journal_series_title">J Neurochem</span>, (submitted)</div> <div class="article_info">R Smith, P Klein, H Chung, K Bacos, RLM Faull, HJ Waldvogel, H Mulder, P Brundin and JY Li. <span class="article_issue_date"></span>. <span class="article_title">Loss of active zone proteins, a sign of synaptic deficiency in Huntington’s disease.</span> (manuscript)</div> <div class="article_info">R Smith, K Bacos, D Soulet, H Walz, S Obermüller, A Lindqvist, M Björkqvist, P Klein, P Brundin, H Mulder and JY Li. <span class="article_issue_date"></span>. <span class="article_title">Disruption of post-Golgi transport in Huntington’s disease.</span> (manuscript)</div>

PY - 2007

Y1 - 2007

N2 - Huntington's disease (HD) is a neurodegenerative disease caused by a CAG-triplet expansion in the gene encoding the protein huntingtin. The disease typically starts in mid-life and progresses for 15-20 years. To date no effective treatment is available for curing the disease. HD primarily affects the striatum, cerebral cortex and hypothalamus. At later stages cell death is evident in the striatum and cerebral cortex. Interestingly, some non-neuronal tissues such as muscle and the endocrine pancreas are also affected. A larger than normal proportion of HD patients develop diabetes mellitus. Traditionally the majority of symptoms were believed to be caused by extensive neuronal death. However, recent studies indicate that neuronal dysfunction plays a central role for symptom development at the early to middle stages of the disease. In this thesis we have aimed at (1) studying the proteins involved in neurotransmitter docking and release at the active zones of the presynapse in patient samples and mouse models of HD; (2) assessing the function of the cholinergic neurons in HD and (3) investigating the intracellular transport and release of insulin in insulin-secreting clonal beta-cells expressing wild-type or mutant huntingtin. We describe a loss of several proteins important for vesicle docking and neurotransmitter release in patient brain samples and in brains from mouse models of HD. Moreover, we have observed a defective synthesis and packaging of acetylcholine in a mouse model of HD and in patient brain tissues. Taken together, these studies indicate that there is a defective neurotransmitter handling and release. Possibly this could underlie some of the cognitive defects and the progressive dementia that are integral parts of HD symptomatology. In beta-cells we detected an early reduction of insulin release in mutant huntingtin expressing cells. The decreased insulin secretion is not explained by decreased insulin synthesis or cell death due to mutant huntingtin. Instead we observed a slowed intracellular transport of insulin-containing vesicles. We suggest that this, in combination with a decreased insulin production, could cause diabetes mellitus in mouse models of HD and in patients. In summary, we have observed alterations in the intracellular transport, neurotransmitter synthesis, handling and release in cell and mouse models of HD and in HD patient brains. The data indicate that cellular dysfunction, rather than cell death, may underlie some of the early symptoms of HD. This suggests that enhancing synaptic functions may be a novel approach to therapeutic intervention in HD.

AB - Huntington's disease (HD) is a neurodegenerative disease caused by a CAG-triplet expansion in the gene encoding the protein huntingtin. The disease typically starts in mid-life and progresses for 15-20 years. To date no effective treatment is available for curing the disease. HD primarily affects the striatum, cerebral cortex and hypothalamus. At later stages cell death is evident in the striatum and cerebral cortex. Interestingly, some non-neuronal tissues such as muscle and the endocrine pancreas are also affected. A larger than normal proportion of HD patients develop diabetes mellitus. Traditionally the majority of symptoms were believed to be caused by extensive neuronal death. However, recent studies indicate that neuronal dysfunction plays a central role for symptom development at the early to middle stages of the disease. In this thesis we have aimed at (1) studying the proteins involved in neurotransmitter docking and release at the active zones of the presynapse in patient samples and mouse models of HD; (2) assessing the function of the cholinergic neurons in HD and (3) investigating the intracellular transport and release of insulin in insulin-secreting clonal beta-cells expressing wild-type or mutant huntingtin. We describe a loss of several proteins important for vesicle docking and neurotransmitter release in patient brain samples and in brains from mouse models of HD. Moreover, we have observed a defective synthesis and packaging of acetylcholine in a mouse model of HD and in patient brain tissues. Taken together, these studies indicate that there is a defective neurotransmitter handling and release. Possibly this could underlie some of the cognitive defects and the progressive dementia that are integral parts of HD symptomatology. In beta-cells we detected an early reduction of insulin release in mutant huntingtin expressing cells. The decreased insulin secretion is not explained by decreased insulin synthesis or cell death due to mutant huntingtin. Instead we observed a slowed intracellular transport of insulin-containing vesicles. We suggest that this, in combination with a decreased insulin production, could cause diabetes mellitus in mouse models of HD and in patients. In summary, we have observed alterations in the intracellular transport, neurotransmitter synthesis, handling and release in cell and mouse models of HD and in HD patient brains. The data indicate that cellular dysfunction, rather than cell death, may underlie some of the early symptoms of HD. This suggests that enhancing synaptic functions may be a novel approach to therapeutic intervention in HD.

KW - neurodegeneration

KW - Neurology

KW - neuropsychology

KW - neurophysiology

KW - Neurologi

KW - cholinergic neuron

KW - exocytosis

KW - transmitter release

KW - intracellular transport

KW - insulin

KW - Huntington's disease

KW - synapse

KW - neuropsykologi

KW - neurofysiologi

M3 - Doctoral Thesis (compilation)

SN - 978-91-85559-91-6

PB - Ruben Smith, Inst. för Experimentell Medicinsk Vetenskap, Lunds Universitet

ER -