臺灣博碩士論文加值系統

第七型脊髓小腦性運動失調症(Spinocerebellar ataxia type 7;SCA7)是第七型運動失調質(ataxin-7)之基因突變所導致的遺傳型顯性神經元病變，它屬於因基因中CAG核酸序列之增長引起的多麩酸胺性運動障礙疾病(polyglutamine neurological disorders)之一。第七型脊髓小腦性運動失調症主要會影響腦幹，視網膜以及小腦，但是在疾病進行的同時，可能也會影響到其它的中樞結構。在腦部神經元中，SCA7基因的產生物：第七型運動失調質，會表現於細胞質及細胞核中。正常第七型運動失調質在N-terminal domain含有4- 35個麩酸胺，引起第七型脊髓小腦性運動失調症的突變第七型運動失調質在N-terminal domain卻含有37-307個麩酸胺。
目前認為轉錄異常(Transcriptional dysregulation)可能是引起多麩酸胺性運動障礙疾病的重要致病機轉之一。最近的研究指出，正常的第七型運動失調質是組成哺乳類TFTC/STAGA共同轉錄活化子化合物(transcription coactivator complexes)所不可或缺的成分。TFTC/STAGA共同轉錄活化子化合物被認為是藉由乙醯化組織蛋白(histones)來活化轉錄的作用，因此猜測正常的其功能之一是和調節基因的表現有關係。因此，有可能是因為突變的多麩酸胺性第七型運動失調質會使得原來正常的第七型運動失調質所調節的轉錄功能受到損壞，連帶的其相關的轉錄因子(transcription factors)或是轉錄共同子( co-factors)也會受到損壞，而改變中樞神經元的基因表現。此外，突變第七型運動失調質也可能經由與其它多麩酸胺性轉錄因子(polyglutamine-rich transcription factor)異常作用或抑制蛋白酶體系統(proteasome system)的活性，進而引起轉錄異常。因此為了證明這個假說，我們利用寡核苷酸微陣列技術(microarray technique)探討第七型脊髓小腦性運動失調症基因轉殖鼠之小腦基因的表現變化。
藉由比對非基因轉殖鼠和表現有第七型運動失調質75個麩酸胺(ataxin-7-Q75)的基因轉殖鼠其小腦基因的變化，發現有些基因有明顯的下降調節，包括有：中樞髓磷脂相關蛋白質(central myelin-related proteins)，轉錄因子Olig1 bHLH protein (Olig1)，分子伴護蛋白 (molecular chaperones)，鈣離子結合蛋白的鈣蛋白酶(calpain, small subunit 1)，泛素-蛋白酶體系統(ubiquitin proteasome system)的泛素羧基末端水解酶L1(ubiquitin carboxy-terminal hydrolase L1)，囊泡蛋白(vesicular proteins)，微管相關蛋白2C (microtubule-associated protein 2C；MAP2C)，軸突運輸相關運動蛋白(motor proteins involved in axon transport)， 磷脂酶D亞型(phospholipase D subtypes )，磷脂酰肌醇-4-磷酸 5-激酶第二型(phosphatidylinositol-4-phosphate 5-kinase, type II,，內向整流鉀通道 KIR4.1 (inward rectifier potassium channel KIR4.1)，運鐵蛋白(transferrin)，分泌粒蛋白Ⅱ(secretogranin II)，金屬蛋白酶組織內的抑制子第二型(tissue inhibitor of metalloproteinase-2 ；TIMP-2)。表現有突變的第七型運動失調質75個麩酸胺(ataxin-7-Q75)的基因轉殖鼠其小腦基因有些基因有明顯的上升調節，包括有：RNA結合蛋白(RNA binding proteins)，突觸性胞吐調節子第二型(synaptic exocytosis regulator 2；Serg2；RIM2)，麩胺酸AMPA亞型接受體2 (glutamate AMPA receptor 2；GluR-2)，接頭樣蛋白(Adaptor-like protein) reduced expression 3 (Rex3)，膜相關性鳥苷酸環化酶(membrane-associated guanylate cyclase) membrane protein, palmitoylated 3(Mpp3)。 上述基因的表現變化應該會引起小腦神經元的功能異常及後續的運動失調症。
我們的實驗証實轉錄異常是突變第七型運動失調質引起第七型脊隨小腦性運動失調症的致病機轉的重要致病機轉之一。進一步對於突變第七型運動失調質引起轉錄異常之分子機轉的研究結果可被用於發展治療第七型脊隨小腦性運動失調症的方法。

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurological disorder and caused by CAG trinucleotide repeat expansion within the coding region of SCA7 gene. Ataxin-7, SCA7 gene product, is an intracellular protein and is widely distributed in the brain and peripheral tissues. Normally, ataxin-7 contains 4-35 glutamines at the N-terminal domain, and polyglutamine tract of disease-causing ataxin-7 expands to 37-306 glutamines. Despite the wide distribution of ataxin-7 in the brain, SCA7 neurodegeneration is only found in the cerebellum (Purkinje cells, molecular and granular layers), inferior olive, pons, anterior horn of spinal cord and retina.
Accumulating data indicates that nuclear expression of polyglutamine-expanded proteins is required for the pathogenesis of polyglutamine neurodegenerative disorders and that the resulting transcriptional abnormality caused by mutant polyglutamine protein may lead to neurotoxicity. Recent studies reported that wild-type ataxin-7 is an integral component of the mammalian TFTC (TBP-freeTAF-containing complex)/STAGA (SPT3-TAF9-ADA-GCN5 acetyltransferase) transcription coactivator complexes. TFTC/STAGA transcriptional complexes are believed to be involved in transcriptional activation by acetylating histones, suggesting that one of normal functions of ataxin-7 is regulating gene expressions. Thus, it is possible that mutant polyglutamine ataxin-7 alters gene expressions of affected CNS neurons by impairing transcriptional regulatory function of wild-type ataxin-7. Mutant ataxin-7 could also causes transcriptional abnormality by inhibiting proteasome activity or sequestering polyglutamine-rich transcription factors or co-factors through aberrant interactions. It is still unknown whether mutant polyglutamine ataxin-7 induces neurotoxicity in vivo by impairing the normal pattern of transcription in affected brain regions. To test this hypothesis, in the present study microarray analysis was performed to detect altered gene expressions in the cerebellum of SCA7 transgenic mouse expressing mutant ataxin-7-Q75.
Our results indicated that compared to control non-transgenic mice, altered expressions of genes involved in myelin formation, oligodendrocyte development, ubiquitin-proteasome pathway, synaptic transmission, signal transduction, intracellular Ca++ signaling, neuronal differentiation, axon transport and regulating neuronal survival or death were observed in the cerebellum of ataxin-7-Q75 transgenic mice.
In summary, the present study provides the evidence that polyglutamine-expanded ataxin-7-Q75 causes transcriptional dysregulation in the cerebellum and resulting cerebellar dysfunction and ataxia. Future investigation of molecular mechanisms underlying ataxin-7-Q75-induced transcriptional abnormality should shed a light on the pathogenic mechanism of SCA7 and lead to a development of possible therapeutic strategies for SCA7.

Acknowledgments iv
Abstract (Chinese) v
Abstract (English) ix
Abbreviations xi
Contents
I. Introduction 1
II. Specific aims 6
III. Methods and Materials 7
3.1 Generation of transgenic mice expressing mutant polyglutamine-expanded
ataxin-7 7
3.2 Identification of transgenic animals by Southern blotting of tail DNA 8
3.3 Western blot analysis of transgene expression in brain 8
3.4 Immunocytochemical staining 9
3.5 Behavioral tests 10
3.6 Microarray analysis 11
3.7 Real-time quantitative RT-PCR assay 12
3.8 Statistics 13
IV. Results 14
4.1 Generation of transgenic mice expressing human disease-causing ataxin-7 14
4.2 Transgene expression 15
4.3 Ataxin-7-Q75 transgenic mice exhibit various ataxic symptoms of motor
dysfunction 15
4.4 Neuropathological analysis of ataxin-7-Q75 transgenic mice 16
4.5 Microarray analysis of altered gene expressions in the cerebellum of
ataxin-7-Q75 mice 17
4.6 Downregulated gene expressions in ataxin-7-Q75 transgenic mice 18
4.7 Upregulated gene expressions in ataxin-7-Q75 transgenic mice 22
4.8 Confirmation of microarray data by real-time RT-PCR assays 23
V. Disscussion 25
VI. References 35
VII. Figures and Tables

Abou-Sleymane G, Chalmel F, Helmlinger D, Lardenois A, Thibault C, Weber C, Mérienne K, Mandel JL, Poch O, Devys D, Trottier Y (2006) Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program. Hum. Mol. Genet., 15, 691-703.
Al-Bassam J, Ozer RS, Safer D, Halpain S, Milligan RA. (2002) MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol.,157, 1187-1196.
Bonini N.M. (2002) Chaperoning brain degeneration. Proc. Natl. Acad. Sci., 99, 16407-16411.
Chartier A, Benoit B, Simonelig M. (2006) A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1.EMBO J. 25, 2253-2262
Chen SM, Peng GH, Wang XJ, Smith AC, Grote SK, Sopher BL, La Spada AR. (2004) Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxyl-terminal region for nuclear localization. Hum. Mol. Genet.,13, 53-67.
Chen Y,Aulia S, Tang BL. (2006) Myelin-associated glycoprotein-mediated signaling in central nervous system pathophysiology. Mol Neurobiol., 34, 81-92.
Choi J, Levey AI, Weintraub ST, Rees HD,Gearing M, Chin LS, Li L. (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem., 279, 13256-13264.
Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B, Matilla A, Zoghbi HY, Orr HT (1997) Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J. Neurosci. 17, 7385-7395.
Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, Guyenet SJ, Deller T, Westrum LE, Sopher BL, La Spada AR. (2006) Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat. Neurosci., 10, 1302-11.
David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, Agid Y, Mandel JL, Brice A (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nature Genet. 17, 65-70.
David G, Durr A, Stevanin G, Cancel G, Abbas N, Yvert G, Benomar A, Belal S, Lebre AS, Abada-Bendib M, Grid D, Holmberg M, Yahyaoui M, Hentati F, Chkill T, Agid Y, Brice A (1998) Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy. Hum. Mol. Genet.,7, 165-170.
Deak F, Schoch S, Liu X, Sudhof TC, Kavalali ET. (2004) Synaptobrevin is essential for fast synaptic-vesicle endocytosis. Nat Cell Biol., 6, 1102-1108.
Doughman RL, Firestone AJ, Anderson RA. (2003) Phosphatidylinositol phosphate kinase put PI4,5P(2) in its place. J. Membr. Biol, 194, 77-89.
Duenas A.M., Goold R., Giunti P (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain, 129, 1357-1370.
Everett CM, Wood NW (2004) Trinucleotide repeats and neurodegenerative disease. Brain 127, 2385-2405.
Gasser MC, Berti I, Hauser KF, Fischer-Colbrie R, Saria A. (2003) Secretoneurin promotes pertussis toxin-sensitive neurite outgrowth in cerebellar granule cells. J Neurochem., 85, 662-669.
della Gaspera B, Pham-Dinh D, Roussel G, Nussbaum JL, Dautigny A. (1998) Membrane topology of the myelin/oligodendrocyte glycoprotein. Eur J Biochem., 258, 478-84.
Gatchel J.R. and Zoghbi H.Y. (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nature Rev. Genetics, 6, 743-755.
Gavarini S, Becamel C, Altier C, Lory P, Poncet J, Bockaert J, Marin P. (2006) Opposite effects of PSD-95 and MPP3 PDZ proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability. Mol Biol Cell., 17, 4619-4631.
Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Harem L, Jenkins NA, Copeland NG, Kakizuka A, Sharp AH, Ross CA, Mouton PR and Colomer V. (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J. Neurosci., 24, 10266-10279.
Hay D.G., Sathasivam K., Tobaben S., Stahl B., Marber M., Mestril R., Mahal A., Smith D.L., Woodman B. and Bates G.P. (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet., 13, 1389 - 1405.
Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, Miguet L, Potier N, Van-Dorsselaer A, Wurtz JM, Mandel JL, Tora L, Devys D (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum. Mol. Genet. 13, 1257-1265.
Helmlinger D, Tora L, Devys D (2006)Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet., 22, 562-70.
Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K,Kubo T, Kurachi Y. (2001) An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol., 281, C922-C931.
Hioki H., Fujiyama F., Taki K., Tomioka R., Furuta T., Tamamaki N. and Kaneko T. (2003) Differential distribution of vesicular glutamate transporters in the rat cerebellar cortex. Neuroscience, 117, 1-6.
Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci., 6, 201-211
Holmberg M, Duyckaerts S, Durr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trittier Y, Hirsh EC, Agid Y, Brice A (1998) Spinocerbellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet., 7, 913-918.
Inoue K. (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics., 6, 1-16.
Ishihara K., Yamagishi N., Saito Y., Adachi H., Kobayashi Y., Sobue G., Ohtsuka K. and Hatayama T (2003) Hsp105suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J. Biol. Chem., 278, 25143-25150.
Jaworski DM, Soloway P, Caterina J, Falls WA (2006) Tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice display motor deficits. J. Neruobiol.,66, 82-94.
Katsuno M., Sang C., Adachi H., Minamiyama M., Waza M., Tanaka F., Doyu M. and Sobue G. (2005) Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc. Natl. Acad. Sci. U S A. 102, 16801-16806.
Kaytor MD, Duvick LA, Skinner PJ, Koob MD, Ranum LPW, Orr HT (1999) Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum. Molec. Genet. 8, 1657-1664.
Klein J (2005) Functions and pathophysiological roles of phospholipase D in the brain. J. Neurochem., 94, 1473-1487.
Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersh SM, Clark HB Zoghbi HY, Orr HT. (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell, 95, 1-20.
La Spada AR, Fi YH, Sopher BL, Libby RT, Wang XJ, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ptacek LJ, Chen SM (2001) Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces con-rod dystrophy in a mouse model of SCA7. Neuron, 31, 913-927.
Lebre AS, Brice A (2003) Spinocerebellar ataxia 7. Cytogenet Genome Res., 100, 154-163.
Ligon KL, Fancy SPJ, Franklin RJM, Rowitch DH. (2006) Olig gene function in CNS development and disease. Glia., 54, 1-10
Lindenberg KS, Yvert G, Müller K, Landwehrmeyer GB (2000) Expression analysis of ataxin-7 mRNA and protein in human brain: Evidence for a widespread distributionand focal protein accumulation. Brain Pathol, 10, 385-394.
Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum. Mol. Genet., 9, 1259-1271.
Luthi-Carter R, Strand A, Hanson SA, Kooperberg C, Schilling G, La Spada AR, Merry De, Young AB, Ross CA, Borchelt DR, Olson JM (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s mouse models reveal context-independent effects. Hum. Mol. Genet., 11, 1927-1937.
Martin JJ, van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, Evrard P, Ceuterick C, Tassuignon MT, Smet-Dieleman H, Van Broeckhoven, C. (1994) On a autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta. Neuoropathol, 88, 277-286.
Masliah E, Rockenstein E, Veinbergs E, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L.(2000) Dopaminergic loss and inclusion body formation in -synuclein mice: implications for neurodegenerative disorders. Science, 287, 1265-1269
Mauger C, Del-Favero J, Ceuterick C, Lubke U, van Broeckhoven C, Martin JJ (1999) Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody. Mol. Brain Res., 74, 35-43.
McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry DE, Chai YH, PaulsonH, Sobue G, Fischbeck KH (1998) CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet., 9, 2197-2202.
Michalik A, Van Broeckhoven C (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Hum. Mol. Genet. 12, R173-R186.
McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR 3rd, Grant PA (2005) Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc. Natl. Acad. Sci. USA, 102, 8478-8482.
Muchowski P.J. and Wacker J.L. (2005) Modulation of neurodegeneration by molecular chaperones. Nature Rev. Neurosci., 6, 11 - 22
Okazawa H (2003) Polyglutamine diseases: a transcription disorder? Cell. Mol. Life Sci. 60, 1427-1439.
Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT,La Spada AR, Roeder RG. (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc. Natl. Acad. Sci. USA, 102, 8472-8477.
Rogers DC, Fisher EMC, Brown SDM, Peters J, Hunter A J, Martin JE (1997) Behavioral and functional analysis of mouse phenotypes: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mammalian Genome, 8, 711-713.
Ross C. A. (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron, 35, 819-822.
Sasahara M, Fries JWU, Rainee EW, Gown AM, Westrum LE, Frosch MP, Bonthron DT, Ross R, Collins T. (1991) PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell, 64, 217-227.
Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell ,95, 55-66.
Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet., 13, 2535-2543.
Strom AL, Forsgren L, Holmberg M. (2005) A role for both wild-type and expanded ataxin-7 in transcriptional regulation. Neurobiol. Dis., 20, 646-655.
Sorimachi H, Ishiura S, Suzuki K. (1997) Structure and physiological function of calpains. Biochem. J., 326, 721-732.
Sow A, Lamant M, Bonny JM, Larvaron P, Piaud O, Lecureuil C, Fontaine I, Saleh MC, Garcia Otin AL, Renou JP, Baron B, Zakin M, Guillou F. (2006) Oligodendrocyte differentiation is increased in transferrin transgenic mice. J Neurosci Res.,83, 403-14.
Sugars KL, Rubinsztein DC (2003) Transcriptional abnormalities in Huntington’s disease. Trends in Genet. 19, 233-238.
Sun L, Bittner MA, Holz RW (2003) Rim, a component of the presynaptic active zone and modulator of exocytosis, binds 14-3-3 through its N terminus. J Biol Chem., 278, 38301- 38309
Sutherland LC, Rintala-Maki ND, White RD, Morin CD. (2005) RNA binding motif (RBM) proteins: a novel family of apoptosis modulators. J Cell Biochem. 94, 5-24.
Tanemura K, Murayama M, Akagi T, Hashikawa T, Tominaga T, Ichikawa M, Yamaguchi H, Takashima A. (2002) Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J. Neurosci., 22, 133-141.
Tsai HF, Lin SJ, Li C, Hsieh M (2005) Decreased expression of Hsp27 and Hsp70 in transformed lymphoblastoid cells from patients with spinocerebellar ataxia type 7. Biochem. Biophys. Res. Commun., 2005;334, 1279-1286
Vallee RB, Williams JC, Varma D, Barnhart LE. (2004) Dynein: an ancient motor protein involved in multiple modes of transport. J.Neurobiol., 58, 189-200.
Vilar M, Murillo-Carretero M,Mira H, Magnusson K, Besset V, Ibanez CF. (2006) Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle. EMBO J., 25, 1219-1230.
Vlkolinsky R, Cairns N,Fountoulakis M, Lubec G. (2001)Decreased brain levels of 2',3'-cyclic nucleotide-3'-phosphodiesterase in Down syndrome and Alzheimer's disease. Neurobiol. of Aging, 22, 547-53
Wang HL, Chang WT, Hsu CY, Huang PC, Chow YW, Li A (2002) Identification of two C-terminal amino acids, Ser355 and Thr357, required for short-term homologous desensitization of -opioid receptors. Biochem.Pharmacol., 64, 257-266.
Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, Huang PC, Li A (2006) Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-xL. Cellular Signalling 18, 541-552.
Wang HL, He CY, Chou AH, Yeh TH, Chen YL, Chou AH, Li A (2007) Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-B p65 and impairs NF-B activity by inhibiting proteasome activity of cerebellar neurons. Cellular Signalling, 19, 573-581.
Watase K., Weeber E. J., Xu B., Antalffy B., Yuva-Paylor L., Hashimoto K., Kano M., Atkinson R., Sun Y., Armstrong D. L., Sweatt J. D., Orr H., Paylor R. and Zoghbi H. Y. (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron, 34, 905-919.
Xin M, Yue T, Ma Z, Wu F, Gow A, Lu QR (2005) Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J. Neurosci., 25, 1354 – 1365.
Yeh TH, Hwang HM, Chen JJ, Wu T, Li A, Wang HL (2005) Glutamate transporter function of rat hippocampal astrocytes is impaired following the global ischemia. Neurobiology of Disease, 18, 476-483.
Yoo SY, Pennesi ME, Weeber EJ, Xu BS, Atkinson R, Chen SM, Armstrong DL, Wu SM, Sweatt JD, Zoghbi HY(2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron, 37, 383-401.
Yool D, Montague P, McLaughlin M, McCulloch MC, Edgar JM, Nave KA, Davies RW, Griffiths IR,McCallion AS. (2002) Phenotypic analysis of mice deficient in the major myelin protein MOBP, and evidence for a novel Mobp isoform. Glia, 39, 256-267
Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci., 23, 213-247.
Zoghbi HY, Botas J (2002) Mouse and fly models of neurodegeneration. Trends in Genet., 18, 463-471.