罕見中樞神經退化性疾病-亞歷山大氏症 (Alexander disease)，其致病原因為位於中樞神經系統當中的星狀細胞內的骨架蛋白-神經膠質纖維酸性蛋白質(Glial fibrillary acidic protein, GFAP) 於基因層次發生突變，導致GFAP於蛋白質層次無法形成正常絲狀結構，並在星狀細胞中產生大量且不正常蛋白質-羅森塔爾纖維 (Rosenthal fibers)，進而導致星狀細胞結構發生改變，無法輔助神經細胞生長與訊號傳遞以及清除腦部廢物等功能，最終使得整個中樞神經系統運作受損。
一個GFAP基因上的點突變如何造成星狀細胞功能異常以及整個中樞神經系統受到影響，其中的機制仍不明確，因此，我的論文將深入探討與亞歷山大氏症相關的病理特徵-羅森塔爾纖維 (Rosenthal fibers)，以及GFAP基因轉殖鼠(GFAP Tg mice) 於星狀細胞形成羅森塔爾纖維 (Rosenthal fibers)的可能原因。
我的論文研究共分為三大部分:
第一部分 (Chapter 3) : 為了進行針對GFAP蛋白質的研究，首先，我將GFAP抗體進行epitope mapping，準確得知所使用的多個GFAP單株抗體的特殊抗原辨識位，有助於往後分析GFAP fragment, GFAP isoform, 辨別來自不同物種的GFAP蛋白質(Mouse GFAP/ Rat GFAP or human GFAP)。
第二部分 (Chapter 4) : 前人因為一隻GFAP基因轉殖鼠(GFAP Tg mice)得知亞歷山大氏症疾病起因為GFAP基因突變所造成，但是，此隻GFAP基因轉殖鼠(GFAP Tg mice)的GFAP基因並沒有突變，而是帶有多個人類正常序列gfap genome，但卻有著與亞歷山大氏症患者相似的病理特徵-羅森塔爾纖維(Rosenthal fibers)於星狀細胞當中，所以，研究團隊對此感到疑惑與不解，因此，我的第二部分研究探討此隻基因轉殖鼠的病理成因，我的研究結果顯示導致此基因轉殖鼠(GFAP Tg mice)產生羅森塔爾纖維(Rosenthal fibers)原因為其GFAP protein major form與其餘原本少數表現的GFAP protein isoform比例失衡，導致GFAP蛋白質無法形成正常絲狀，進而聚集成團塊形成羅森塔爾纖維(Rosenthal fibers)，所以有著與亞歷山大氏症患者相似的病理特徵，但是，為何GFAP protein major form與GFAP protein isoform的表現量失衡，其中的機制仍不明確，待往後更進一步探討。
第三部分 (Chapter 5) : 已知GFAP蛋白質降解路徑為泛素-蛋白酶體系統 (Ubiquitin-proteasome system, UPS)，所以，在亞歷山大氏症病患或是此疾病的模式生物中可以偵測到泛素(Ubiquitin)表現量大量上升，但是，並未確切得知是否為GFAP被接上泛素(Ubiquitin)，因為，使用能認mono-Ubiquitin抗體以及生化分析技術，所以，我的研究得知確實亞歷山大氏症病患或是此疾病的模式生物的GFAP確實被接上泛素(Ubiquitin)，但是，為何無法有效清除被接上泛素(Ubiquitin)的GFAP，則需要進一步作分析與探討。
我的研究結果初步解答與亞歷山大氏症相關的病理特徵，但是對於其機制仍需要深入探討，期望在未來能解出此謎團，讓病患能得到一絲希望。

Glial fibrillary acid protein (GFAP) is an intermediate filament (IF) protein expressed predominantly in mature astrocytes of the central nervous system (CNS). Astrocytes are specialized glial cells expressing GFAP, which together with other IF proteins, form glial filaments that function as a signaling platform and a structural scaffold that makes astrocytes to serve as a guardian cell of the CNS. Although elevated GFAP expression is involved with almost all insults to the CNS, no convincing evidence of a primary astrocyte disease caused by GFAP elevation had been demonstrated until the unexpected finding that transgenic mice engineered to constitutively overexpress a human Gfap transgene exhibited a lethal phenotype. That GFAP accumulates in the form of Rosenthal fibers in astrocytes of these mice similar to those observed in patients with AxD. leads to the discovery that mutations in the GFAP gene cause Alexander disease (AxD). This is a primary genetic disorder of astrocytes often affects the entire CNS, and its distinctive neuropathology consists of abundant Rosenthal fibers that accumulate throughout the cytoplasm of astrocytes. Although the link between GFAP mutation and AxD is firmly established, how a cytoskeletal defect in astrocytes affecting their functions or interactions with other cells could cause brain catastrophe remains unknown. However, characterization of mutant GFAP as the likely initiating event at least focuses my attention on how best to approach these questions.
The goal of this study is to investigate the means by which AxD mutations lead to GFAP aggregation, astrocyte dysfunction, and severe consequences for other CNS cell types. In the first part of my study, I have developed experimental tools to enable these studies. One set of tools was to map the epitopes of a panel of commonly used anti-GFAP antibodies that could be useful in detecting biochemically modified forms of GFAP in samples from human AxD patients and mouse AxD models. Another set was to isolate primary astrocytes from GFAP knockout (KO) rats and GFAP transgenic mice to study the effect of GFAP mutations and overexpression on astrocyte pathology. In the second part of my study, I have determined the role of increased GFAP isoform expression in protein aggregation and astrocyte dysfunction. In the third part of my study, I have identified and characterized pathologically modified forms of GFAP in a rodent model of AxD and in human AxD patients.
These studies provide novel information on the pathological significance of aberrant GFAP not just in astrocytes but also in the other cells with which they interact, and suggest mechanisms by which primary astrocyte dysfunction leads to AxD and other neurological disorders with glial involvement.

Chapter 1
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139. Hagemann, T. L., Jobe, E. M., and Messing, A. (2012) Genetic ablation of Nrf2/antioxidant response pathway in Alexander disease mice reduces hippocampal gliosis but does not impact survival. PLoS One 7, e37304
140. Pekny, T., Faiz, M., Wilhelmsson, U., Curtis, M. A., Matej, R., Skalli, O., and Pekny, M. (2014) Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease. APMIS 122, 76-80
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142. Hagemann, T. L., Gaeta, S. A., Smith, M. A., Johnson, D. A., Johnson, J. A., and Messing, A. (2005) Gene expression analysis in mice with elevated glial fibrillary acidic protein and Rosenthal fibers reveals a stress response followed by glial activation and neuronal dysfunction. Hum Mol Genet 14, 2443-2458
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154. Minkel, H. R., Anwer, T. Z., Arps, K. M., Brenner, M., and Olsen, M. L. (2015) Elevated GFAP induces astrocyte dysfunction in caudal brain regions: A potential mechanism for hindbrain involved symptoms in type II Alexander disease. Glia 63, 2285-2297
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chapter 2
1. Lin, N. H., Huang, Y. S., Opal, P., Goldman, R. D., Messing, A., and Perng, M. D. (2016) The role of gigaxonin in the degradation of the glial-specific intermediate filament protein GFAP. Mol Biol Cell 27, 3980-3990
2. Lin, N. H., Jian, W. S., Snider, N., and Perng, M. D. (2024) Glial fibrillary acidic protein is pathologically modified in Alexander disease. J Biol Chem 300, 107402
3. Lin, N. H., Messing, A., and Perng, M. D. (2017) Characterization of a panel of monoclonal antibodies recognizing specific epitopes on GFAP. PLoS One 12, e0180694
4. Lin, N. H., Yang, A. W., Chang, C. H., and Perng, M. D. (2021) Elevated GFAP isoform expression promotes protein aggregation and compromises astrocyte function. FASEB J 35, e21614

Chapter 3
1. Lin, N. H., Messing, A., and Perng, M. D. (2017) Characterization of a panel of monoclonal antibodies recognizing specific epitopes on GFAP. PLoS One 12, e0180694
2. Brenner, M., Johnson, A. B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J. E., and Messing, A. (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27, 117-120
3. Goldman, J. E., and Corbin, E. (1988) Isolation of a major protein component of Rosenthal fibers. Am J Pathol 130, 569-578
4. Heaven, M. R., Flint, D., Randall, S. M., Sosunov, A. A., Wilson, L., Barnes, S., Goldman, J. E., Muddiman, D. C., and Brenner, M. (2016) Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease. J Proteome Res 15, 2265-2282
5. Pekny, T., Faiz, M., Wilhelmsson, U., Curtis, M. A., Matej, R., Skalli, O., and Pekny, M. (2014) Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease. APMIS 122, 76-80
6. Tian, R., Gregor, M., Wiche, G., and Goldman, J. E. (2006) Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease. Am J Pathol 168, 888-897
7. Iwaki, T., Iwaki, A., and Goldman, J. E. (1993) Alpha B-crystallin in oxidative muscle fibers and its accumulation in ragged-red fibers: a comparative immunohistochemical and histochemical study in human skeletal muscle. Acta Neuropathol 85, 475-480
8. Iwaki, T., Kume-Iwaki, A., Liem, R. K., and Goldman, J. E. (1989) Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. Cell 57, 71-78
9. Albrechtsen, M., von Gerstenberg, A. C., and Bock, E. (1984) Mouse monoclonal antibodies reacting with human brain glial fibrillary acidic protein. J Neurochem 42, 86-93
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Chapter 4
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Chapter 5
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Chapter 6

1. Alexander, W. S. (1949) Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 72, 373-381, 373 pl
2. Verkhratsky, A., Sofroniew, M. V., Messing, A., deLanerolle, N. C., Rempe, D., Rodriguez, J. J., and Nedergaard, M. (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN neuro 4
3. Messing, A. (2019) Refining the concept of GFAP toxicity in Alexander disease. J Neurodev Disord 11, 27
4. Hagemann, T. L. (2022) Alexander disease: models, mechanisms, and medicine. Current opinion in neurobiology 72, 140-147