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Studies on novel protein complexes composed of major schizophrenia susceptibility factors, Dysbindin and DRD2

이설애 (Seol-Ae Lee, 포항공과대학교)

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초록 moremore
Schizophrenia is a severe chronic illness that affects approximately 0.5%~1% of the world’s population. While a number of theories have been suggested to delineate the etiology of schizophrenia, accumulating evidence has indicated schizophrenia as a neurodevelopmental disorder, which is supported by...
Schizophrenia is a severe chronic illness that affects approximately 0.5%~1% of the world’s population. While a number of theories have been suggested to delineate the etiology of schizophrenia, accumulating evidence has indicated schizophrenia as a neurodevelopmental disorder, which is supported by multiple observations including compromised cell structure and impoverished neural connectivity. Over the past two decades, extensive molecular genetic studies identified multiple susceptibility genes for schizophrenia including Dystrobrevin-binding protein 1 (DTNBP1) and Disrupted-in-Schizophrenia-1 (DISC1) genes, both of which have been implicated in neuronal development. Recently, several lines of evidence have suggested that it is unlikely that a single gene causes schizophrenia, and more likely that a group of multiple genes, possibly interacting, are involved. However, the understanding of protein components and the molecular mechanism underlying the potential link in etiology of schizophrenia have remained elusive. In this study, I demonstrated the functional collaboration of Dystrobrevin-binding protein 1 (dysbindin, encoded by DTNBP1) and DISC1 in the neurite outgrowth, which is a major component of neurodevelopmental process. Moreover, I elucidated the mechanism which involves fine-tuned degradation of dysbindin by DISC1, thereby suggesting a convergent pathway where dysbindin and DISC1, two schizophrenia-associated proteins, cooperate in neurodevelopmental process. Furthermore, I focused on the functional relevance of Histone deacetylase 6 (HDAC6), dysbindin and DISC1 in neurite outgrowth. Several lines of evidence have indicated that HDAC6 is implicated in diverse neuronal functions including neurite extension and polarization. Although the growing evidence indicates that HDAC6 is involved in nervous system, the entire interactors and function of HDAC6 in the neuronal development have remained poorly understood. In the present study, I identified HDAC6 as a common binding partner of dysbindin and DISC1 by its deacetylase catalytic domains. Notably, the defects in nerite outgrowth caused by either knockdown of DISC1 and dysbindin were rescued by HDAC6 co-expression. In addition, I characterized dysbindin as a major microtubule-associated protein using biochemical and immunocytochemical analyses. These results suggest that HDAC6 plays a key role in neurite outgrowth in collaboration with dysbindin and DISC1 proteins. Finally, I investigated a functional relationship of Tetraspanin-7 (TSPAN7) and dopamine D2 receptor (DRD2). On the basis of the ‘dopamine hypothesis of schizophrenia’ stating that hyperactivity of the dopamine system is responsible for the psychotic symptoms, converging lines of evidence have supported important roles of DRD2-mediated signaling in the neurochemical pathogenesis of schizophrenia. Since DRD2-mediated signaling is finely-tuned by functional surface expression, identifying the molecules and mechanism that modulate trafficking of DRD2 is crucial to understand the neurochemical pathology of psychiatric disorders including schizophrenia. In the present study, I suggested TSPAN7 as a novel regulator of DRD2-mediated signaling. Over-expression of TSPAN7 resulted in reduced surface level of DRD2 that was accompanied by promoted internalization of DRD2 TSPAN7. Indeed, co-expression of TSPAN7 with DRD2 abolished the activation of ERK upon dopamine treatment, collectively implicating that TSPAN7 has a potential to modulate dopamine signaling by regulation of surface trafficking of DRD2. In summary, I demonstrated a functional link between dysbindin and DISC1, two schizophrenia associated proteins, as well as an essential role of HDAC6 in neurite outgrowth as a novel component of the protein complex containing dysbindin and DISC1. Moreover, I suggested TSPAN7 as a novel regulator of dopaminergic signaling, which exerts a critical role in neurochemical pathology of schizophrenia, by modulating trafficking of DRD2. Finally, I expect that these findings add to our understanding of molecular mechanism underlying neurodevelopmental pathogenesis of schizophrenia and aberrant dopamine transmission in schizophrenia.
목차 moremore
I. General Introduction
1-1. Neurochemical pathology of schizophrenia ------------------------------ 1
1-2. Neurodevelopmental pathology of schizophrenia -------------------------- 3
...
I. General Introduction
1-1. Neurochemical pathology of schizophrenia ------------------------------ 1
1-2. Neurodevelopmental pathology of schizophrenia -------------------------- 3
1-3. Dystrobrevin-binding protein 1 (dysbindin) ------------------------------ 4
1-4. Disrupted-in-Schizophrenia 1 (DISC1) --------------------------------- 7
1-5. The emerging roles of HDAC6 in nervous system -------------------------- 10
1-6. Objective -------------------------------------------------------- 12
1-7. Figures -------------------------------------------------------- 15
1-8. Tables --------------------------------------------------------- 21

II.DISC1 regulates the dysbindin function by enhancing its stability.
2-1. Introduction ------------------------------------------------------ 22
2-2. Methods --------------------------------------------------------- 24
2-3. Results ---------------------------------------------------------- 30
2-4. Discussion ------------------------------------------------------- 37
2-5. Figures ---------------------------------------------------------- 41

III. HDAC6 plays a key role in neurite outgrowth in collaboration with dysbindin and DISC1 proteins.
3-1. Introduction ------------------------------------------------------ 51
3-2. Methods --------------------------------------------------------- 52
3-3. Results ---------------------------------------------------------- 57
3-4. Discussion ------------------------------------------------------- 61
3-5. Figures ---------------------------------------------------------- 65

IV. Identification of Tetraspanin-7 as a novel regulator of dopamine D2 receptor (DRD2) trafficking
4-1. Introduction ------------------------------------------------------ 73
4-2. Methods --------------------------------------------------------- 75
4-3. Results ---------------------------------------------------------- 80
4-4. Discussion ------------------------------------------------------- 85
4-5. Figures ---------------------------------------------------------- 88

국문요약 (Summary in Korean) ------------------------------------------- 96
References ---------------------------------------------------------- 112
Acknowledgement ----------------------------------------------------- 115
Curriculum Vitae ------------------------------------------------------ 119