第十七型脊髓小腦萎縮症年輕轉殖小鼠聲門功能異常之研究

Abstract

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.