(This is the first of a series of four posts in which I will briefly describe the mechanisms of neurodegenerative diseases and propose a new idea for neurodegenerative drug development. 這是四篇系列文章中的第一篇，在這個系列文章中，我將簡要科普神經退行性疾病的機制，並提出一個神經退行性藥物開發的新思路。)

Protein aggregation, an ancient phenomenon, even occurs before the formation of earliest cells. Under the action of cosmic radiation and lightning, some simple amino acids naturally form and synthesize proteins. These early proteins often combine to form non-functional aggregates.

蛋白質聚集，一個古老的現象，在細胞形成之前，在宇宙輻射與雷電作用下一些簡單的胺基酸自然形成并合成蛋白質，這些早期蛋白質就經常結合在一起形成無功能的聚集。

Early life was just a few fragile Ribozymes, self-replicating or replicating each other, adsorbed on the surface of the crystal or phospholipid membrane (I'll go into more detail in the third article) [1]. These early protein aggregates floated away and adsorbed with nucleic acids and phospholipid membranes, producing a more catalytic ribozyme that eventually formed early cells [1].

早期的生命只是一些脆弱的核酶，自複製或相互的複製，吸附在結晶或磷脂膜的表面（在第三篇文章中我會做更多詳細介紹）。這些早期的蛋白質聚集體飄來飄去，與核酸和磷脂膜相互吸附，產生了催化功能更強的核酶，最終形成了早期的細胞[1]。

However, when protein aggregates appear in nerve cells which with complex function and long-lived, they become terrible killers, causing nerve cells to die and spread between cells. This leads to neurodegenerative diseases.

然而，當蛋白質聚集體出現在功能複雜而又長壽的細胞——神經細胞中時，卻成為了可怕的殺手，導致神經細胞的死亡并在細胞間傳播。這就導致了神經退行性疾病。

(This picture is from 「Trying uniform 」/「Wake up」[pixiv])

In early cells, on the one hand, due to the simple function of cells, the effect of intracellular protein aggregation on cell function is relatively small. In addition, by division, single-celled organisms can produce a protein-aggregating cell that is about to die and a cell that does not carry protein aggregation, thereby eliminating protein aggregation in new cells.

在早期的細胞中，一方面由於細胞的功能簡單，所以細胞內蛋白質聚集對細胞功能的影響較小。此外，單細胞生物可以通過分裂產生一個即將死亡的攜帶蛋白質聚集的細胞和一個不攜帶蛋白質聚集的細胞，由此消除新細胞中的蛋白質聚集。

In complex animals, long-lived and specialized nerve cells are needed to maintain motor function and memory. The death of a large number of nerve cells will lead to the death of the organism, therefore they are sensitive to protein aggregation but cannot eliminate protein aggregation by these way.

而在複雜的動物中，需要長壽而特化的神經細胞來維持運動功能和記憶，神經細胞的大量死亡就會導致生物體死亡，因而對蛋白質聚集敏感但又無法通過這些方式清除掉蛋白質聚集。

As ribosomes and tRNAs are evolved, specialized proteins for catalysis, namely enzymes, could be made. The nucleic acid is responsible for the genetic and the enzyme is responsible for the catalysis. This model is significantly more competitive than the model of ribozyme responsible for genetics and catalysis, so most of the ribozymes disappear under competitive pressure, leaving only a few important ribozymes such as ribosomes[2].

隨著核糖體與tRNA被進化出來，可以製造專門的用於催化的蛋白質，也就是酶。核酸負責遺傳而酶負責催化的模式，其競爭力明顯高於核酶同時負責遺傳和催化，所以大部分的核酶在競爭壓力下消失了，只留下核糖體等少數重要的核酶[2]。

Early codons may only correspond to relatively simple water-soluble amino acids. Proteins formed by these amino acids are also less prone to aggregation. But more complex and poorly water-soluble amino acids are more likely to clump together, allowing proteins to form "pockets." And amino acids that are easily oxidized can expand the catalytic reaction species of the protein. Therefore, in competition, codons corresponding to these amino acids gradually won [3].

早期的密碼子可能只對應著較為簡單的易溶於水的胺基酸。由此形成的蛋白質也較為不容易發生聚集。但是更複雜且難溶於水的胺基酸更容易聚集在一起，可以使蛋白質形成“口袋”。而容易被氧化的胺基酸可以擴展蛋白質的催化反應種類。因此在競爭中，可以對應於這些胺基酸的密碼子，逐漸勝出[3]。

However, these amino acids also make proteins more susceptible to aggregation. The water-insoluble amino acid can cause proteins to aggregate with each other if exposed to the surface of the protein, and the amino acid which is easily oxidized is more likely to be damaged by oxidative factors to destroy the folded structure of the protein.

但是這些胺基酸也使蛋白質更容易發生聚集。不溶於水的胺基酸如果暴露在蛋白質表面可以促使蛋白質相互聚集，而易被氧化的胺基酸更可能被氧化因素損傷從而破壞蛋白質的折疊結構。

And due to the increasingly complex functions within the cell, specialized proteins need to be transported to a specific location, and the wrong place itself may cause protein aggregation based on differences in chemical environments such as pH.

由於細胞內的功能越來越複雜，需要把專門的蛋白質運送到專門的地點，送錯地方本身可能基於PH值等化學環境的差異導致蛋白質聚集。

A protein with a signal peptide ensures a more precise transport. However, the protein will be folded together with the signal peptide to form a functional structure under the physical mechanism, and then the signal peptide is cleaved off at the destination. Since the signal peptide has been removed, the structure that the protein has maintained is no longer physically most stable. This also increases the likelihood that the protein structure will be damaged and then aggregate.

如果蛋白質帶有一段信號肽可以保證更精確的轉運。但是蛋白質會帶著信號肽一起在物理機制下完成折疊形成功能結構，然後在目的地切掉信號肽，由於去掉了信號肽后蛋白質已經維持的結構已經不再是物理最穩定的。這也增加了蛋白質結構被損傷然後發生聚集的可能性。

Proteins called intrinsically disordered proteins (IDPs) are retained in the genome because of the advantages of performing more functions while synthesizing fewer proteins to save energy. These proteins normally remain partially unfolded to function in combination with more variety of proteins, but at the same time partially unfolded regions make these proteins more susceptible to aggregation [4].

因為在盡量合成更少的蛋白以節省能量的前提下執行更多的功能帶來的優勢，被稱為本質無序蛋白質（IDPs）的蛋白質被保留在在基因組中。這些蛋白平時保持著部分未折疊的狀態以與多種蛋白質結合發生功能，但與此同時部分未折疊的區域使這些蛋白更容易發生聚集[4]。

In addition, some structurally regular protein aggregation is utilized to accomplish specific functions, such as microtubules, phosphorylated tubulin and related proteins can be aggregated to form microtubules. Phosphorylation at one end of the microtubules causes aggregation and dephosphorylation at the other end causes deagglomerate, thereby prolonging the microtubules in the direction of dephosphorylation.

此外，一些結構規律的蛋白質聚集被利用於完成特定的功能，例如微管，磷酸化的微管蛋白與相關蛋白可以聚集在一起形成微管。在微管的一端磷酸化使其聚集，另一端去磷酸化使其解聚，就可以使微管向去磷酸化的方向延長。

These functionally and easily-aggregated proteins increase the risk of abnormal protein aggregation, such as phosphorylated Tau, a microtubule-associated intrinsically-disordered-protein, appears in protein aggregates in Alzheimer's dementia and Frontotemporal dementia [5] [6] [7], and is also recruited into PrpSc in Prion disease [8]. Tau can be recruited into protein aggregates in different neurodegenerative diseases, which also enhances microtubule damage in these diseases and appears macroscopically as a reduction in axons.

這些承擔功能而又容易聚集的蛋白質增加了形成異常蛋白質聚集的風險，例如磷酸化的Tau蛋白，一種微管相關的本質無序蛋白，就出現在阿爾茲海默氏癡呆、額顳葉癡呆的蛋白質聚集體中[5][6][7]，並且在Prion病中也被募集到PrpSc中[8]。Tau可以在不同的神經退行性疾病中被募集到蛋白聚集體中，這反過來又加強了這些疾病中的微管損傷，并在宏觀上表現為神經軸突的減少。

Another point to note is that at the micro level, collisions between molecules are not as elastic as macro-level collisions, molecules always collide with each other randomly and do Brownian motion. Every protein molecule is like in a chaos ocean composed of protein molecules, waiting for one of these random collisions is appropriate to complete mutual recognition and form the correct structure or step by step to reach the correct position under the interference of random collisions.

還有一點需要注意的是在微觀層次，分子之間的碰撞都不是像宏觀層次碰撞這樣是彈性的，分子總會在不斷的隨機相互碰撞，做布朗運動。每一個蛋白質分子就像在一個混亂的海洋中，等待這些隨機的碰撞之中有一次是合適的，以完成它們之間的相互識別並形成正確結構或一步一步的在隨機碰撞的干擾之下到達正確的位置。

Therefore, None of the above mentioned mechanisms of protein transport and deaggregation can ensure that 100% of the protein arrives at the correct location and deagglomerates. It can only guarantee that the correct proportion is controlled within a certain range, and There are always some proteins that can evade monitoring based on these mechanisms.

因此，以上任何蛋白質運輸和解聚的機制都無法保證蛋白質100%的為到達正確的位置并解聚，只能保證正確的比例被控制在一定範圍，總有漏網之魚。

It can be seen that accumulation of protein aggregation in complex cells over time is inevitable.

由此可見，複雜細胞中蛋白聚集隨著時間而積累幾乎是不可避免的。

And our cells are not sitting still, they regularly process aggregated proteins through a number of specific mechanisms, and even use these mechanisms to form various cycles within the cell.

而我們的細胞也不是坐以待斃，它們通過另外幾套特定機制定期處理掉聚集的蛋白質，甚至利用這些機制形成了細胞內各種週期。

However, these mechanisms are all ineffective in neurodegenerative diseases. In the next post I will briefly describe these mechanisms and why they fail.

然而這些機制在神經退行性疾病中卻全部失效了。在下一篇文章我將簡要介紹這些機制以及它們為什麼會失效。

References 參考文獻

[1] RNA worlds: from life's origins to diversity in gene regulation[M]. New York;: Cold Spring Harbor Laboratory Press, 2011.

[2] Eigen M, Schuster P. The hypercycle: a principle of natural self-organization[M]. Springer Science & Business Media, 2012.

[3] Why are there 20 amino acids?

[4] Uversky V N. Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators[J]. Frontiers in molecular biosciences, 2014, 1: 6.

[5] Sjögren M, Davidsson P, Tullberg M, et al. Both total and phosphorylated tau are increased in Alzheimer's disease[J]. Journal of Neurology, Neurosurgery & Psychiatry, 2001, 70(5): 624-630.

[6] Sabbagh J J, Dickey C A. The metamorphic nature of the tau protein: Dynamic flexibility comes at a cost[J]. Frontiers in neuroscience, 2016, 10: 3.

[7] Zhu S, Shala A, Bezginov A, et al. Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble[J]. PLoS One, 2015, 10(3): e0120416.

[8] Reiniger L, Lukic A, Linehan J, et al. Tau, prions and Aβ: the triad of neurodegeneration[J]. Acta neuropathologica, 2011, 121(1): 5-20.