脊髓小腦萎縮症第17型轉殖小鼠之呼吸變異性與聲門功能異常

Abstract

脊髓小腦萎縮症（spinocerebellar ataxia）是一種體染色體顯性遺傳的神經退化疾病。脊髓小腦萎縮症各型的基因表現不同、臨床上的病徵上也各型不一，但主要病因皆是小腦的區域產生損傷，尤其是Purkinje cells。脊髓小腦萎縮症第十七型的致病因子則是由於TATA-box結合蛋白（TATA-box binding protein; TBP）有不正常的CAG三核苷擴增，臨床上的症狀包含了行動遲緩、運動失調局部張力不全、眼球震顫、發聲與吞嚥困難、以及認知功能障礙。發聲與吞嚥的動作與呼吸道肌肉的調節有著密切關係，有些患者於疾病晚期在進食時因為異物進入呼吸道而引起吸入性肺炎，病因而導致死亡，因此可能暗示了聲門，甚至是呼吸功能的調節有異常的情形。但是臨床上有關於脊髓小腦萎縮症第十七型呼吸功能的研究卻甚少。本研究是利用whole body plethysmography 來測量這些未拘束之清醒脊髓小腦萎縮症第十七型轉殖小鼠的呼吸功能，並與正常野生型小鼠相比較，以瞭解呼吸是否發生異常情形，並於麻醉的模式下以辣椒素興奮其肺迷走神經C纖維，引起反射，觀察其喉返神經的變化。實驗結果發現，脊髓小腦萎縮症第十七型轉殖小鼠於出生後的第三週出現呼吸不規律，呼吸週期變異性大，且呼吸頻率較慢的現象。但是在給予3%或5％二氧化碳刺激之後這個呼吸變異性會逐漸降低至與野生型無顯著差異。此外，投予0.625 μg/kg以及1.25 μg/kg之辣椒素興奮肺迷走神經C纖維引起肺化學反射，結果是野生型小鼠呼吸暫停，支配聲門運動的喉返神經活性增強，但是轉殖小鼠在興奮後的呼吸暫停時間較短，且喉返神經反應較弱。轉殖小鼠呈現呼吸的變異性以及喉返神經反射性反應微弱，暗示了脊髓小腦萎縮症第十七型轉殖小鼠的呼吸功能與聲門運動的調控是有障礙的。Autosomal dominant spinocerebellar ataxias（SCA）are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affects the Purkinje cells in cerebellum. Spinocerebellar ataxia type 17 (SCA17) is one of the neurodegenerative diseases which display cytosine-adenine-guanine (CAG) repeat expansion coding for polyglutamine tracts in the transcription factor TATA box-binding protein (TBP). Clinical symptoms of patients with SCA17 display ataxia, dystonia, bradykinesia, cognitive impairment, dysphonia and dysphagia. Dysphonia and dysphagia may implicate that their regulatory mechanism of the vocal folds and respiratory system may have been malfunctioned. We aimed to examine whether the vocal fold movements and respiratory function of the SCA17 transgenic (Tg) mice was dysfunctional. Respiratory pattern was evaluated with a whole body plethysmography under unrestraint and unanesthesia. Pressure fluctuation representing respiratory pattern was recorded through a differential pressure transducer and amplifier and then stored in the hard disc via PowerLab system. We also observed the activity of the recurrent laryngeal nerve (RLNA) in response to capsaicin-induced activation of pulmonary vagal C-fiber receptor in Tg mice. Results obtained revealed that Tg mice displayed a prolonged and significantly varied respiratory duration at the third week after postnatal development. This respiratory variability was much reduced in the challenge to the increase in CO2 at a level of 3% or 5% CO2 condition. Additionaly, administration of capsaicin (0.625 and 1.25 μg/kg) produced pulmonary chemoreflex characterized by apnea, and also an enhancement of RLNA during period of apnea in wild-type mice. However, apnea and RLNA enhancement induced by capsaicin administration was much less in Tg mice, suggesting that modulation of vocal fold movement might be dysfunctional. These results indicate that respiratory functions of Tg mice with SCA 17 symptom may have been disordered, and the respiratory control mechanism of Tg mice with SCA 17 may have been disorder.