1. 磷酸酶PTP-3/LAR通過調控SYD-2/Liprin-α分子內折疊抑制UNC-104/KIF1A的激活
細胞胞器、蛋白質與其他胞內貨物的運輸，以及貨物在胞內特定位置的停泊，是透過使用細胞骨架中微管 (MT)與肌動蛋白纖維軌道，由馬達蛋白如驅動蛋白、動力蛋白與肌球蛋白來執行。馬達蛋白的正常運作，對於維持細胞的功能、極性、發育、遷移與分裂等至關重要。驅動蛋白家族(KIF)的馬達蛋白是正端導向的，它們將貨物(如突觸囊泡、粒線體、RNA顆粒等)從微管的負端運輸到正端。KIF1A(即C. elegans中的UNC-104)，屬於驅動蛋白-3家族，已知能夠在快速的軸突運輸機制中運輸STVs(運輸蛋白質突觸囊泡)。調節驅動馬達蛋白的機制包含”選擇性補充”、”調和活動”和”拔河”。目前還尚未完全釐清驅動蛋白的調控。一種已知的機轉是透過與小的轉接蛋白的交互作用，可以活化驅動蛋白。Liprin-α(即C. elegans中的SYD-2)，近期顯示它透過本身的SAM結構域與UNC-104的FHA結構域交互作用來活化UNC-104。而Liprin-α/SYD-2作為LAR/PTP-3的受質(它是一種白血球共同抗原相關的受體蛋白酪氨酸磷酸酶)，已知會與磷酸化的liprin-α作用。在C. elegans中，缺乏ptp-3會導致SYD-2的Y741被過度磷酸化。因此，本論文中假設PTP-3調控SYD-2分子內摺疊來激活UNC-104。
事實上，在CoIP試驗中，發現了UNC-104與SYD-2在缺乏PTP-3的線蟲裂解液中的交互作用增加了。目前已知SYD-2會經歷分子內折疊，並且所使用的FRET分析揭露SYD-2在ptp-3的突變體中，主要是以開放式的結構存在。不可磷酸化的SYD-2 (Y741F)在ptp-3的突變體中過度表現，導致大部分變為摺疊的SYD-2，另外磷酸模擬的SYD-2 (Y741E)突變體，則主要導致在開放式的結構中。重要的是，可以在 運輸減少的神經元的軸突和突觸中觀察到SNB-1 STV被保留在細胞體內，且可能是ptp-3突變體中SYD-2與UNC-104表現量減少的結果。此外，已知子神經元束軸突上UNC-104馬達蛋白聚集(密度)，然而在syd-2突變體，馬達蛋白聚集顯著地減少。ptp-3突變體中，UNC-104與其貨物(SNB-1 STVs)的順行運輸速度顯著增加而停滯時間減少。即使馬達蛋白和貨物的速度都增加了，淨移動距離並無顯著差異，可能是因方向改變的增加造成拔河現象。最後，上位分析顯示，對於UNC-104馬達蛋白活性的調控，PTP-3是SYD-2的上游。以上結果顯示了，缺乏PTP-3磷酸酶促使SYD-2去磷酸化，進而導致開放的SYD-2構型增加，暴露其與UNC-104交互作用的位點(如C端SAM結構域)，以致馬達蛋白活性增加和快速軸突運輸的增加。

2. 中間絲蛋白 IFB-1的缺陷負面影響秀麗隱桿線蟲(C. elegans)的神經發育、化感器感應神經元中粒線體之定位和運作

粒線體是ATP的合成、鈣離子調節與細胞凋亡的重要胞器。粒線體的長距離雙向運輸倚賴的是微管與微管馬達蛋白；而短距離運輸和停泊是依賴肌動蛋白與肌動馬達蛋白。不過，中間絲蛋白(IFs)不具有相關的馬達蛋白。此外，且很難釐清神經元的IFs與粒線體的移動性是否有關連。以下的研究中，旨在了解在神經元內粒線體的運輸與中間絲蛋白的關聯。在C. elegans 11種細胞質內中間絲家族的蛋白中， 對於IFB-1最感興趣，因為表現在感覺神經元的次神經元中，並與IFA蛋白形成一個至關線蟲活性的強制的異聚物。IFB-1的缺陷會導致輕微的染料填充缺陷、顯著的趨化性缺陷與生命週期的縮短。在ifb-1(ju71)突變體中，發生粒線體運輸上的缺陷即樹突的發育不良，導致在樹突中發生錯誤的定位。此外，突變體中耗氧量減少還揭示了突變體的粒線體功能上的缺陷。重要的是，共定位與蛋白質體外結合實驗中，顯示了IFB-1與粒線體存在物理性的交互作用。綜上所述，我們提出了一個模型：中間絲蛋白可做為粒線體在C. elegans神經元中運輸過程重要的臨時停泊站。

3. C. elegans的同源神經絲狀蛋白TAG-63可能用於穩定軸突運輸中微管上的突觸囊泡

目前C. elegans的神經絲狀蛋白尚未被鑑定出來，使這種模式生物無法用於研究神經絲相關的神經疾病。於本實驗室近期研究中將暫定為gene-63 (TAG-63)鑑定為C. elegans可能的同源神經絲的三聯肽，透過電子顯微鏡能觀察到TAG-63可形成10 nm的纖維，同時擁有神經絲的重多肽與輕多肽的結構。近期的研究藉由分析基因剔除tag-63的突變體可觀察的表徵使其成為研究神經絲狀蛋白疾病的模式生物。而確實能觀察到tag-63(ok471)的突變線蟲體延遲產卵，並對於觸碰反應有缺陷及減少的咽喉部蠕動。細胞層面的研究則指出，使用購買的人類NEFH抗體進行免疫染色，可以觀察到TAG-63::GFP與免疫染色的螢光訊號共定位。此外，基因減量tag-63抑制了NEFH的免疫染色結果。使用丙烯酰胺處理C. elegans後導致TAG-63表達增加，以及神經元結構的改變，與現存的研究資料一致。另外，在運動記錄器的分析顯示在基因剔除tag-63的動物中，表現出更少的驅動蛋白-3 UNC-104和STV移動的特性。最後，UNC-104馬達蛋白、STV貨物與TAG-63的共定位可透過丙烯酰胺的處理減低。因此，鑑定TAG-63作為同源神經絲狀蛋白，可以作為研究神經絲相關疾病的線蟲模型提供更多可能性。

1.Suppression of UNC-104/KIF1A activation by PTP-3/LAR phosphatase via the regulation of SYD-2/Liprin-α intramolecular folding
Transport of cellular organelles, proteins, and other cellular cargos, as well as docking of cargos at a particular location is carried out by motor proteins such as kinesin, dynein, and myosin, employing cytoskeletal microtubule (MT) and actin filament tracks. Proper function of motor proteins are essential for the maintenance of cellular function, polarity, development, migration, division, etc. Kinesin family (KIF) of motors are plus-end directed, i.e., they transport cargos (such as synaptic vesicles, mitochondria, RNA granules, etc.) from the minus-ends of MT to their plus-ends. KIF1A, also known as UNC-104 in C. elegans, belongs to the kinesin-3 family and is known to shuttle STVs (synaptic vesicle protein transport vesicles) in the fast axonal transport machinery. Several mechanisms for regulation of kinesin motor proteins exist encompassing “selective recruitment”, “coordinated activity” and “tug-of-war”. Yet a complete understanding of kinesin regulation is far from reach. One identified mechanism is kinesin activation by its interaction with small adaptor proteins. Liprin-α, SYD-2 in C. elegans, has been recently shown to interact with UNC-104’s FHA domain via its SAM domain to activate UNC-104. Liprin-α/SYD-2 is a substrate of LAR/PTP-3 (leukocyte common antigen-related receptor protein tyrosine phosphatase) known to interact with phosphorylated liprin-α. In C. elegans, lack of ptp-3 results in hyperphosphorylation of SYD-2 at tyrosine 741. In this doctoral thesis, it is hypothesized that intramolecular folding of SYD-2 is regulated by PTP-3 to activate UNC-104.
Indeed, using CoIP assays, an increased interaction between UNC-104 and SYD-2 in lysates of worms lacking PTP-3 was identified. SYD-2 is known to undergo intramolecular folding and employed intramolecular FRET analysis revealed that SYD-2 predominantly exists in an open conformation state in ptp-3 mutants. A non-phosphorylatable SYD-2 Y741F overexpressed in ptp-3 mutant worms, resulted in predominately folded conformation states of SYD-2 while a phosphomimicking SYD-2 Y741E variant resulted predominantly in open conformational states. Critically, SNB-1 STV cargo retention in somas with decreased trafficking qualities in axons and synapses of neurons were observed, likely as a result of reduced expression of SYD-2 and UNC-104 in ptp-3 mutants. Further, increased UNC-104 motor clustering (density) along axons of sub-lateral neuronal bundles were determined in ptp-3 mutants, however in syd-2 mutants, motor clustering was significantly reduced. Anterograde velocities of both UNC-104 and its cargo (SNB-1-containing STVs) significantly increased in ptp-3 mutants with reduced pausing duration. Interestingly, although speeds of both motor and cargo increased, net run-length of motor and cargo did not change significantly, likely due to increased tug-of-war events indicated by increased directional changes. Lastly, epistatic analysis revealed that PTP-3 is upstream of SYD-2 in regulating UNC-104’s motor activity. These results suggest that lack of PTP-3 phosphatases to dephosphorylate SYD-2 results in increased open SYD-2 conformations, exposing its UNC-104 interaction sites (such as the C-terminal SAM domains) leading to increased motor activation and concomitantly increased fast axonal transport events.

2.Depletion of intermediate filament protein IFB-1 negatively affects neural development, mitochondrial localization and its functionality in amphid sensory neurons of C. elegans
Mitochondria are essential cellular organelles for ATP synthesis, calcium buffering and apoptosis. Long-range bidirectional transport of mitochondria depends on microtubules and microtubule-based motor proteins, while short-range transport and docking mainly relies on actin and actin-based motors. However, intermediate filaments (IFs) do not possess associated motor proteins. Moreover, it is poorly understood whether a link between neuronal IFs and mitochondrial mobility exist. In the following study of Chapter II, the aim is to understand the role of IFs in intraneuronal mitochondrial transport. In C. elegans, among the 11 cytoplasmic IF family proteins, IFB-1 is of particular interest as it is expressed in a subset of sensory neurons and forms an obligate heteropolymer with one of the essential IFA proteins crucial for worm viability. Depletion of IFB-1 leads to mild dye-filling defect, significant chemotaxis defect and a significant reduction in life span. Mislocalization of mitochondria in dendrites of ifb-1(ju71) mutants indicate defects in mitochondrial transport, and dendrites in these mutants are also shorter. Additionally, functional defects of mitochondria can be observed in these mutants with reduced oxygen consumption. Lastly, colocalization and pull-down assay indicates the existence of physical interactions between mitochondria and IFB-1. Taken together, a model is proposed in which intermediate filaments may serve as crucial transient docking stations for mitochondria during their transport in the lengthy neurons of C. elegans.

3.TAG-63 is a neurofilament orthologue in C. elegans with a prospective function to stabilize microtubule-bound synaptic vesicles during axonal transport
Currently, no known neurofilament protein in C. elegans has been characterized, thus rendering this model organism ineffective to study neurofilament related neurological diseases. A recent study from my PI’s lab identified the temporarily assigned gene-63 (TAG-63) in C. elegans as a potential orthologue of the neurofilament triplet peptide. It has been shown that TAG-63 forms 10 nm filaments using electron microscopy, sharing structural features from both neurofilament heavy as well as from neurofilament light peptide. The present study analyses visible phenotypes of a tag-63 knockout mutant with the goal to use it as a model organism to study neurofilament-based diseases. Indeed, tag-63(ok471) mutant worms exhibit not only egg retention phenotypes but also defective touch responses along with reduced pharyngeal pumping. On the cellular level, the present study reports that TAG-63::GFP colocalizes with fluorescent signals gained from whole mount immunostaining using commercial human NEFH antibody. Moreover, knocking down tag-63 reduced the NEFH immunostaining. Treatment of worms with the NF-toxin acrylamide lead to an increase in TAG-63::GFP expression with concomitant structural changes in neurons consistent with similar reports from the literature. Furthermore, kymograph analysis shows reduced kinesin-3 UNC-104 and STV moving properties in tag-63 knockout animals. Lastly, UNC-104 motors and STV cargos clearly colocalize with TAG-63 which can be reduced when treating animals with acrylamide. In summary, identification of TAG-63 as a neurofilament orthologue protein can provide novel opportunities to develop crucial worm models to study neurofilament-related diseases.

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