脊髓小腦萎縮症（Spinocerebellar ataxias；SCA )，是一種漸進性的神經退化性疾病，目前發現有二十八種不同類型，其中第十七型主要症狀是步伐不穩、吞嚥與發音困難、肌肉張力失調、震顫性麻痺、眼球震顫、聽覺遲緩、漸進的癡呆、癲癇等，致病原因是TATA-box結合蛋白(TATA-box binding protein)上的的N端有一段CAG三核苷重複過度擴增，形成過長的多麩醯胺酸 (polyglutamine ; polyQ) 突變蛋白，並引起這種蛋白沉澱，導致細胞毒性，以致於產生神經元退化。吞嚥與發音困難可能與聲門運動功能異常有關，管制聲門運動的神經主要是喉返神經，唯也受到橋腦的調節，臨床上發現脊髓小腦萎縮症的病人，其橋腦也有發生萎縮，橋腦是呼吸調節中樞 (pneumotaxic center)的所在，也涉及聲門運動的調控。我們實驗室過去曾利用SCA17轉殖鼠為實驗材料，發現SCA17轉殖鼠在六個月時，聲門運動的調控機制不佳。問題是六個月的小鼠已經是年老的動物，我要問的問題是年輕轉殖小鼠（二到三個月）是否也會呈現聲門運動調控機制異常，這一點非常重要，可以告訴我們年輕病人是否也有吞嚥與發音的問題。研究分成兩大部分，第一，利用辣椒素刺激肺部的無鞘神經C纖維，引起反射作用，觀察喉返神經呼吸活動的反應，結果發現年輕轉殖小鼠，低劑量辣椒素所引起反射作用是，血壓下降、心跳減慢及呼吸暫停，與野生小鼠無異，在呼吸暫停期間，喉返神經呼氣活性（也稱吸氣後活性）顯著上升，這種上升反應既見於自主呼吸的轉殖小鼠，也發生在麻痺且以人工呼吸機送氣的轉殖小鼠，但是人工送氣下的轉殖鼠，反應卻遠遠小於野生型小鼠;第二是觀察其聲門運動，結果發現，在一般情況下，野生小鼠吸氣時面積顯著大於轉殖鼠，但呼氣時候面積並無差異，在給予辣椒素引起呼吸暫停期間，轉殖小鼠與野生小鼠的聲門都會內收且關閉，在呼吸恢復後回復後的第一次呼吸週期，聲門面積對照面積相比並無差異。這些結果說明，年輕的SCA 17轉殖小鼠其聲門運動對辣椒素引起的反射反應與野生型動物相似，也暗示轉殖小鼠聲門的調控機制可能正常。

Spinocerebellar ataxia (SCA) is a progressing neurodegenerative disease. There have been identified 28 different types. The pathological symptom of the SCA17 shows progressive ataxia, dysphagia and dysphonia, tremor, nystagmus, cognitive decline, psychiatric symptoms, dementia. The SCA 17 is caused by the expansion of CAG repeat of TATA-binding protein, which leads to an abnormal expansion of a polyglutamine stretch in the N-terminal of the corresponding protein. These may result in protein aggregation and contribute to cytotoxicity. Dysphagia and Dysphonia might correlate with vocal fold dysfunction. The vocal fold movements are mainly controlled by the recurrent larynageal nerve (RLN) and regulated also by the pons. In clinics, patients with SCA 17 showed pontine atrophy after death autopsy. In this regard, we had observed that there was a reflexively blunt response of the RLN to capsaicin-induced activation of the pulmonary C-fibers in SCA17 transgenic mice of six-month old. The problem is that the six-month old mice might represent old animal model, suggesting that the glottis may have been mulfunctioned. Whether this blunt response of the RLN to capsaicin administration could be observed in the young transgenic mice is remained to be determined. This is very important since it would implicate that the young patients might have also the opportunity of a dysfunctional swallowing and pronunciation. To answer this question, the present study was divided into two parts. First, the RLN activities were evaluated in response to capsaicin-induced activation of the pulmonary C-fibers in three-month young transgenic mice. The results obtained displayed that there was a similar increase in the RLN during apnea induced by capsaicin administration in transgenic young mice compared with that in the control littermate wild type animals. Second, the glottal movement was investigated in response to capsaicin administration in transgenic mice. The results observed showed that the glottal area during apnea and the first respiratory cycle recovery from apnea initiated by capsaicin administration was the same in transgenic mice as those seen in the control littermate wild type animals. These results indicate that the glottal movement of the young SCA17 transgenic mice may have a similar response to capsaicin administration compared with that in control animals. It may also suggest that the regulatory mechanism of the vocal fold movement is probably still normally functioned in young SCA17 mice.

Abdala AP, Rybak IA, Smith JC, Zoccal DB, Machado BH, St-John WM, and Paton JF. 2009. Multiple pontomedullary mechanisms of respiratory rhythmogenesis. Respir Physiol Neurobiol 168(1-2):19-25.
Alheid GF, Milsom WK, and McCrimmon DR. 2004. Pontine influences on breathing: an overview. Respir Physiol Neurobiol 143(2-3):105-114.
Barnes PJ. 1986. Neural control of human airways in health and disease. Am Rev Respir Dis 134(6):1289-1314.
Bauer P, Laccone F, Rolfs A, Wullner U, Bosch S, Peters H, Liebscher S, Scheible M, Epplen JT, Weber BH et al. . 2004. Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype. J Med Genet 41(3):230-232.
Bech S, Petersen T, Norremolle A, Gjedde A, Ehlers L, Eiberg H, Hjermind LE, Hasholt L, Lundorf E, and Nielsen JE. 2010. Huntington's disease-like and ataxia syndromes: identification of a family with a de novo SCA17/TBP mutation. Parkinsonism Relat Disord 16(1):12-15.
Boon JA, and Milsom WK. 2010. The role of the pontine respiratory complex in the response to intermittent hypoxia. Respir Physiol Neurobiol 171(2):90-100.
Burk K. 2007. Cognition in hereditary ataxia. Cerebellum 6(3):280-286.
Chang YC, Lin CY, Hsu CM, Lin HC, Chen YH, Lee-Chen GJ, Su MT, Ro LS, Chen CM, and Hsieh-Li HM. 2011. Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. J Neurochem.
Dutschmann M, and Herbert H. 2006. The Kolliker-Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off-switch and upper airway resistance in rat. Eur J Neurosci 24(4):1071-1084.
Dutschmann M, Menuet C, Stettner GM, Gestreau C, Borghgraef P, Devijver H, Gielis L, Hilaire G, and Van Leuven F. 2010. Upper airway dysfunction of Tau-P301L mice correlates with tauopathy in midbrain and ponto-medullary brainstem nuclei. J Neurosci 30(5):1810-1821.
Dutschmann M, Morschel M, Kron M, and Herbert H. 2004. Development of adaptive behaviour of the respiratory network: implications for the pontine Kolliker-Fuse nucleus. Respir Physiol Neurobiol 143(2-3):155-165.
Dutschmann M, and Paton JF. 2002. Inhibitory synaptic mechanisms regulating upper airway patency. Respir Physiol Neurobiol 131(1-2):57-63.
Gao R, Matsuura T, Coolbaugh M, Zuhlke C, Nakamura K, Rasmussen A, Siciliano MJ, Ashizawa T, and Lin X. 2008. Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17. Eur J Hum Genet 16(2):215-222.
Gatchel JR, and Zoghbi HY. 2005. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6(10):743-755.
Hage SR, and Jurgens U. 2006. Localization of a vocal pattern generator in the pontine brainstem of the squirrel monkey. Eur J Neurosci 23(3):840-844.
Hagenah JM, Zuhlke C, Hellenbroich Y, Heide W, and Klein C. 2004. Focal dystonia as a presenting sign of spinocerebellar ataxia 17. Mov Disord 19(2):217-220.
Hubner J, Sprenger A, Klein C, Hagenah J, Rambold H, Zuhlke C, Kompf D, Rolfs A, Kimmig H, and Helmchen C. 2007. Eye movement abnormalities in spinocerebellar ataxia type 17 (SCA17). Neurology 69(11):1160-1168.
Kalia M. 2003. Dysphagia and aspiration pneumonia in patients with Alzheimer's disease. Metabolism 52(10 Suppl 2):36-38.
Kim JY, Kim SY, Kim JM, Kim YK, Yoon KY, Lee BC, Kim JS, Paek SH, Park SS, Kim SE et al. . 2009. Spinocerebellar ataxia type 17 mutation as a causative and susceptibility gene in parkinsonism. Neurology 72(16):1385-1389.
Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, Yamada M, Takahashi H, and Tsuji S. 1999. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8(11):2047-2053.
Lee KZ, Fuller DD, Lu IJ, Lin JT, and Hwang JC. 2007. Neural drive to tongue protrudor and retractor muscles following pulmonary C-fiber activation. J Appl Physiol 102(1):434-444.
Lee LY, and Pisarri TE. 2001. Afferent properties and reflex functions of bronchopulmonary C-fibers. Respir Physiol 125(1-2):47-65.
Lee TH, Lee JG, Yon JM, Oh KW, Baek IJ, Nahm SS, Lee BJ, Yun YW, and Nam SY. 2011. Capsaicin prevents kainic acid-induced epileptogenesis in mice. Neurochem Int 58(6):634-640.
Lin IS, Wu RM, Lee-Chen GJ, Shan DE, and Gwinn-Hardy K. 2007. The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment. Parkinsonism Relat Disord 13(4):246-249.
Lu IJ, Lee KZ, and Hwang JC. 2006. Capsaicin-induced activation of pulmonary vagal C fibers produces reflex laryngeal closure in the rat. J Appl Physiol 101(4):1104-1112.
Lu IJ, Lee KZ, Lin JT, and Hwang JC. 2005. Capsaicin administration inhibits the abducent branch but excites the thyroarytenoid branch of the recurrent laryngeal nerves in the rat. J Appl Physiol 98(5):1646-1652.
Morris JB, Symanowicz PT, Olsen JE, Thrall RS, Cloutier MM, and Hubbard AK. 2003. Immediate sensory nerve-mediated respiratory responses to irritants in healthy and allergic airway-diseased mice. J Appl Physiol 94(4):1563-1571.
Mueller S, Riedel HD, and Stremmel W. 1997. Direct evidence for catalase as the predominant H2O2 -removing enzyme in human erythrocytes. Blood 90(12):4973-4978.
Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, and Kanazawa I. 2001. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10(14):1441-1448.
Nunez-Abades PA, Portillo F, and Pasaro R. 1990. Characterisation of afferent projections to the nucleus ambiguus of the rat by means of fluorescent double labelling. J Anat 172:1-15.
Pedroso JL, Braga-Neto P, Felicio AC, Aquino CC, Prado LB, Prado GF, and Barsottini OG. 2011. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr 69(2):253-257.
Perlman SL. 2004. Symptomatic and disease-modifying therapy for the progressive ataxias. Neurologist 10(5):275-289.
Reetz K, Gaser C, Klein C, Hagenah J, Buchel C, Gottschalk S, Pramstaller PP, Siebner HR, and Binkofski F. 2009. Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson's disease. Mov Disord 24(1):99-103.
Reetz K, Lencer R, Hagenah JM, Gaser C, Tadic V, Walter U, Wolters A, Steinlechner S, Zuhlke C, Brockmann K et al. . 2010. Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17. Cerebellum 9(2):210-217.
Reid SJ, Rees MI, van Roon-Mom WM, Jones AL, MacDonald ME, Sutherland G, During MJ, Faull RL, Owen MJ, Dragunow M et al. . 2003. Molecular investigation of TBP allele length: a SCA17 cellular model and population study. Neurobiol Dis 13(1):37-45.
Rolfs A, Koeppen AH, Bauer I, Bauer P, Buhlmann S, Topka H, Schols L, and Riess O. 2003. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol 54(3):367-375.
Schwarzacher SW, Rub U, and Deller T. 2011. Neuroanatomical characteristics of the human pre-Botzinger complex and its involvement in neurodegenerative brainstem diseases. Brain 134(Pt 1):24-35.
Shah AG, Friedman MJ, Huang S, Roberts M, Li XJ, and Li S. 2009. Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17. Hum Mol Genet 18(21):4141-4152.
Smith JC, Abdala AP, Koizumi H, Rybak IA, and Paton JF. 2007. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J Neurophysiol 98(6):3370-3387.
Song G, and Poon CS. 2009. Lateral parabrachial nucleus mediates shortening of expiration and increase of inspiratory drive during hypercapnia. Respir Physiol Neurobiol 165(1):9-12.
Sriranjini SJ, Pal PK, Krishna N, and Sathyaprabha TN. 2009. Subclinical pulmonary dysfunction in spinocerebellar ataxias 1, 2 and 3. Acta Neurol Scand.
St-John WM, and Paton JF. 2004. Role of pontile mechanisms in the neurogenesis of eupnea. Respir Physiol Neurobiol 143(2-3):321-332.
Stransky A, Szereda-Przestaszewska M, and Widdicombe JG. 1973. The effects of lung reflexes on laryngeal resistance and motoneurone discharge. J Physiol 231(3):417-438.
Szereda-Przestaszewska M, and Wypych B. 1996. Laryngeal constriction produced by capsaicin in the cat. J Physiol Pharmacol 47(2):351-360.
Weissbach A, Djarmati A, Klein C, Dragasevic N, Zuhlke C, Rakovic A, Guzvic M, Butz E, Tonnies H, Siebert R et al. . 2010. Possible genetic heterogeneity of spinocerebellar ataxia linked to chromosome 15. Mov Disord.
Widdicombe JG. 1995. Neurophysiology of the cough reflex. Eur Respir J 8(7):1193-1202.
Zealear DL, Garren KC, Rodriguez RJ, Reyes JH, Huang S, Dokmeci MR, and Najafi K. 2001. The biocompatibility, integrity, and positional stability of an injectable microstimulator for reanimation of the paralyzed larynx. IEEE Trans Biomed Eng 48(8):890-897.
Zuhlke C, and Burk K. 2007. Spinocerebellar ataxia type 17 is caused by mutations in the TATA-box binding protein. Cerebellum:1-8.

林孟緯，2008。脊髓小腦萎縮症第十七型轉殖小鼠之呼吸變異性與聲門功能異常。國立台灣師範大學生命科學系碩士論文。

吳上豪，2001。過度表現過氧化氫分解基因轉殖小白鼠的心血管參數。中原大 學醫學工程學系碩士論文。