近日，一個關於帕金森氏症細胞病理機轉的新證據被多家媒體報導：台灣的神經科學研究團隊透過特殊基因株的果蠅和小鼠的腦細胞，證實GAK/aux基因是神經膠質細胞中主導溶酶體降解α-synuclein(α-突觸核蛋白)的關鍵。這立刻引起我的興趣，我想說哇，距2012年丹麥神經科學家Maiken Nedergaard提出膠淋巴系統，花了12年，終於有新消息了。
Recently, new evidence of Parkinson’s disease neuropathology has gained significant attention from various media platforms. A team of Taiwanese neuroscientists has confirmed through studies using brain cells of special strains of fruit flies and mice that the GAK/aux plays the key role in the lysosomal pathway that contributes to SNCA/α-synuclein degradation in glia cells. This immediately sparked my curiosity, and I thought, wow, 12 years after Danish neuroscientist Maiken Nedergaard proposed the 'glymphatic system' in 2012, now we have something new.
報導寫很精簡，領隊的教授表示，2017年已發現GAK/aux基因在帕金森氏症中可能發揮關鍵作用，這次研究則是進一步證實，GAK/aux基因是透過維持溶酶體的酸性環境來調節α-synuclein降解，就像溶酶體的酸性調節開關；此開關一旦失效，溶酶體就無法進行清除。論文原文有提到，GAK基因透過磷酸化調控溶酶體膜上V-ATPase的組裝，它是一種由ATP驅動的質子泵，將質子(H+)轉運至細胞膜，因此能夠維持溶酶體需要的pH3~5環境。
The news is written very concisely. The leading professor said in the interview that it’s known in 2017 that GAK/aux gene may play a key role in the development of Parkinson's disease. And this study further confirmed that the GAK/aux gene regulates the degradation of α-synuclein by maintaining the acidic environment of lysosomes, just like an acidity-dependent switch of lysosomes; once this switch fails, the clearance system goes down. In the original paper, it shows that the gene orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase, which is a proton pump driven by ATP (transporting protons to the cell membrane). Therefore, it can maintain the pH 3~5 environment required by lysosomes.
訪問中表示這項發現非常重要，因為它告訴我們，只要能讓這個開關恢復作用，膠質細胞就能重新運作，清除毒蛋白，這將是未來開發帕金森氏症治療藥物的潛在新靶點。但我的疑問是，這樣還是沒有解釋到，為何開關壞掉了？
It was said in the interview that this discovery is very important because it tells us that as long as we can restore this switch, we can make glial cells resume their work to remove toxic proteins, which indicates that GAK will be a potential new target for the development of new drugs that cure Parkinson's disease. But it puzzles me, as it still does not explain why the switch fails.
科學家是透過人為剔除基因的果蠅和小鼠來證明這個基因對溶酶體路徑很重要。但人類身上發生的帕金森氏症應該是不同狀況。單純基因突變導致的帕金森氏症很罕見。只有5~10%的帕金森氏症患者具有明確家族史，基因突變只是帕金森氏症的眾多可能病因之一，而且，更多相關的致病基因又陸續被發現，包括顯性或隱性遺傳的基因。此外，還有另一種遺傳危險因子――單一核苷酸多型性，例如常見於亞洲人種的顯性遺傳LRRK2基因上G2385R變異點。然而，這些都只表示可能增加患病的機率，但不一定會發病。有疾病的基因和發病是兩件事。
The scientists used fruit flies and mice with a specific knocked-out gene to prove that this gene is important in the lysosomal pathway. But it’s a different story for Parkinson's disease in humans. Most Parkinson's disease cases are considered sporadic, meaning they don't have a clear genetic cause, and only 5-10% of Parkinson's patients have a clear family history; few cases are linked to specific gene mutations. And more genes that may contribute to PD have been discovered, including dominant or recessive genes. In addition, there is another genetic risk factor—single nucleotide polymorphism, such as the G2385R mutation point on the dominant LRRK2 gene common in Asians. However, it only indicates that the risk of developing the disease may increase, but not necessarily the cause of it. They are two different things.
目前為止，各種風險因子與帕金森氏症關聯性的驗證顯示，唯一具充分因果關係證據的是「年齡」，但它無法被改變；因果關係已獲部分證實會提高帕金森氏症罹患率的是：
1.年輕時曾暴露於殺蟲劑、除草劑。
2.從事農業、園藝工作者，因為有較高機率經常接觸除草劑或其他環境危險因子。焊接人員(例如不鏽鋼業者) 則是可能長期暴露在高錳濃度的環境。
3.頭部創傷及無意識昏迷時間超過5分鐘。可能因血腦屏障損傷，導致免疫傷害或腦中不正常蛋白質過度增加。
4.曾飲用未煮沸和未經過濾的井水。除了殺蟲劑會從土壤滲透到地下水之外，台灣天然環境中的重金屬含量本來就偏高，這些天然重金屬也會滲透到地下水中。鉻、鎳為蛇紋岩的伴生礦物，而蛇紋岩主要分布在中央山脈東側丘陵地、平原和海岸山脈、零星分布在蘭嶼西北部的集塊岩中。嘉南平原與蘭陽平原的頁岩與黏板岩沖積物中，則含有砷濃度較高的氧化鐵。受安山岩質火山灰母質影響的台北關渡平原與北投、士林一帶，土壤中砷的含量也偏高。
So far, the verified association between various factors and Parkinson's disease shows that the only factor with sufficient causal evidence is "age", but it cannot be changed; and the causal relationship has been partially confirmed to increase the risk of Parkinson's disease are:
1. Exposure to pesticides and herbicides at a young age.
2. Agricultural and gardening workers have a higher chance of frequent exposure to herbicides or other environmental risk factors. Welders (such as stainless steel workers) may suffer from chronic exposure to high manganese concentrations.
3. Head trauma and loss of consciousness for more than 5 minutes. It may cause damage to the blood-brain barrier, leading to immune damage or excessive production of abnormal proteins in the brain.
4. Drinking unboiled and unfiltered well water. In addition to pesticides seeping from the soil into the groundwater, the heavy metal content in Taiwan's natural environment is already high, and these natural heavy metals can also seep into the groundwater. Chromium and nickel are associated minerals of serpentinite, and serpentinite is mainly distributed in the hills, plains and coastal mountains on the east side of the Central Mountain Range, and scattered in the agglomerates in the northwest of the Orchid Island. The shales and clay slates of the Chianan Plain and Yilan Plain contain iron oxides with high arsenic concentrations. The arsenic content is also high in the soil in the Guandu Plain of Taipei, Beitou, and Shilin, due to its origin of andesite volcanic ash.
所以，也許我們不該研發新藥，而是研發好的淨水器，支持有機農業，解決環境污染問題，還有保護好你的頭，不要讓頭被撞擊，避免任何可能造成你昏迷超過五分鐘的因素，還有確實做好職業傷害的防護。
So, maybe we should not develop new drugs, but instead develop better water purifiers, support organic farming, manage environmental pollution, protect your head, don't let it be hit, avoid situations that cause you loss of consciousness for more than five minutes, and implement safety measures in workplaces.
那麼，有什麼中草藥能作用到大腦的溶酶體路徑嗎？薑黃素、杜仲方 (一個以杜仲為主，搭配石斛、生地黃、乾薑的方劑)、韓醫的瓊玉膏(경옥고)、橙皮素(陳皮)、丹皮酚(牡丹皮)、銀杏葉萃取物EGb 761、五味子乙素(北五味子)、白藜蘆醇(虎杖、桑樹的根/皮/葉)，都曾被認為可能有助於腦細胞溶酶體路徑的調節。以前當R跟診，也是有資深教授完全用西醫化合物成份的方式去開中藥的，雖然不敢說百發百中，不過就我觀察他的患者反應，療效也不錯。
What herbal medicine affects the lysosomal pathway in the brain? Curcumin, Duzhong formula (Eucommia bark as main ingredient, along with Dendrobium, Rehmanniae Radix, and dried ginger), Kyung-Ok-Ko (경옥고), as well as compounds like hesperetin (citrus fruits) and paeonol (from Cortex Moutan), EGb 761 (a special extract from ginkgo biloba leaves), Schisandrin B (Schisandra chinensis), and resveratrol (Polygonum cuspidatum and roots, bark, and leaves of mulberry) have been linked to modulation of the lysosomal pathway. I remember during my residency in the hospital, there was a senior professor who prescribed Chinese medicine with only Western medical compounds in mind. I wouldn't say it was always super effective, but based on my observations of his patients' reactions, the treatment was pretty good.
雖然我人生第一篇SCI論文就是針灸的細胞分子機轉，不過中醫在治療帕金森氏症時，有在思考中藥或針灸有沒有作用在這些細胞分子的靶點嗎？我自己是覺得沒有。針灸的細胞分子機轉牽涉很多條路徑（示意圖畫到哭），但要我選一個最直接影響的起點，就是TRPV1接受器了。我記得有進入細胞核和進入粒線體的細胞路徑，但沒有到溶酶體的。也許針灸治療帕金森氏症走的是另外的細胞路徑吧？
Although my first SCI paper was about the molecular mechanisms of acupuncture, I wonder if physicians practising Chinese medicine or acupuncture have any of these molecular targets in mind when treating Parkinson's disease? I personally don't think so. The molecular mechanisms of acupuncture involve many pathways (drawing the diagrams made me cry), but if I were to choose the most direct starting point, it would be the TRPV1 receptor. I remember there are cellular pathways that enter the nucleus and the mitochondria, but not to the lysosomes. Maybe acupuncture treatment of Parkinson's disease takes another cellular pathway?
𓈒𓂂 𓈒
GAK和帕金森氏症的淵源，是因為臨床上有一群與α-synuclein(α-突觸核蛋白)有關的神經退化性疾病，而帕金森氏症是在這之中最著名的一個，其他還有路易氏體失智症、多發性系統萎縮症。這些疾病有個共同的病理特徵，就是α-synuclein異常的聚集和堆積，導致神經元功能障礙和死亡。
GAK基因表達出的GAK蛋白好像還跟囊泡的「脫殼」有關，脫殼就是垃圾囊泡運送到溶酶體後需要打開，把垃圾倒出來，才能被分解掉。這牽涉到網格蛋白(clathrin)媒介的細胞內吞作用，需要GAK蛋白(作為輔因子)與Hsc70(一種「鷹架」蛋白) 和ATP的配合來完成這個動作。GAK基因突變或表達降低，可能會使囊泡的運送、融合/釋放內容物和回收的過程延遲。如果塞滿垃圾囊泡的溶酶體腫大，整個循環和降解的過程都會受到干擾吧？不過這和研究裡講的維持pH值應該是不同件事。
我想太多了。總覺得自己現在對於醫學研究有著難以言說的心結。反正新藥研發出來也只會被人拿去減肥或壯陽吧？人們生病的速度太快了，所謂的治療常常感覺像西西弗斯在做的事情一樣。
𒂗𒆠𒆕
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