Honors & Awards

  • Travel Fellowship Awardee, Taiwan Society of Cell and Molecular Biology (2008)
  • 1st prize poster winner, GRC Conference on Molecular Cellular Neurobiology (2008)
  • Travel Fellowship Awardee, NPAS (Neuroscience Program in Academia Sinica) (2011)
  • 2nd prize poster winner, 1st Asia- Pacific Drosophila Research Conference (2011)
  • Outstanding PhD Thesis Award, National Taiwan University, Taiwan (2012)
  • Dean’s Postdoctoral Fellowship, School of Medicine, Stanford University (2013)
  • Postdoctoral Research Abroad Program fellowship, Taiwan National Science Council (NSC) (2014-2015)

Professional Education

  • Doctor of Philosophy, National Taiwan University (2010)

Stanford Advisors


2012-13 Courses


All Publications

  • PINK1-mediated Phosphorylation of Miro Inhibits Synaptic Growth and Protects Dopaminergic Neurons in Drosophila SCIENTIFIC REPORTS Tsai, P., Course, M. M., Lovas, J. R., Hsieh, C., Babic, M., Zinsmaier, K. E., Wang, X. 2014; 4

    View details for DOI 10.1038/srep06962

    View details for Web of Science ID 000344385100014

  • Neurofibromin Mediates FAK Signaling in Confining Synapse Growth at Drosophila Neuromuscular Junctions JOURNAL OF NEUROSCIENCE Tsai, P., Wang, M., Kao, H., Cheng, Y., Walker, J. A., Chen, R., Chien, C. 2012; 32 (47): 16971-16981


    Neurofibromatosis type I (NF1), caused by the mutation in the NF1 gene, is characterized by multiple pathological symptoms. Importantly, ~50% of NF1 patients also suffer learning difficulty. Although downstream pathways are well studied, regulation of the NF1-encoded neurofibromin protein is less clear. Here, we focused on the pathophysiology of Drosophila NF1 mutants in synaptic growth at neuromuscular junctions. Our analysis suggests that the Drosophila neurofibromin protein NF1 is required to constrain synaptic growth and transmission. NF1 functions downstream of the Drosophila focal adhesion kinase (FAK) Fak56 and physically interacts with Fak56. The N-terminal region of NF1 mediates the interaction with Fak56 and is required for the signaling activity and presynaptic localization of NF1. In presynapses, NF1 acts via the cAMP pathway, but independent of its GAP activity, to restrain synaptic growth. Thus, presynaptic FAK signaling may be disrupted, causing abnormal synaptic growth and transmission in the NF1 genetic disorder.

    View details for DOI 10.1523/JNEUROSCI.1756-12.2012

    View details for Web of Science ID 000311420800040

    View details for PubMedID 23175848

  • Activity-dependent retrograde laminin A signaling regulates synapse growth at Drosophila neuromuscular junctions PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tsai, P., Wang, M., Kao, H., Cheng, Y., Lin, Y., Chen, R., Chien, C. 2012; 109 (43): 17699-17704


    Retrograde signals induced by synaptic activities are derived from postsynaptic cells to potentiate presynaptic properties, such as cytoskeletal dynamics, gene expression, and synaptic growth. However, it is not known whether activity-dependent retrograde signals can also depotentiate synaptic properties. Here we report that laminin A (LanA) functions as a retrograde signal to suppress synapse growth at Drosophila neuromuscular junctions (NMJs). The presynaptic integrin pathway consists of the integrin subunit ?? and focal adhesion kinase 56 (Fak56), both of which are required to suppress crawling activity-dependent NMJ growth. LanA protein is localized in the synaptic cleft and only muscle-derived LanA is functional in modulating NMJ growth. The LanA level at NMJs is inversely correlated with NMJ size and regulated by larval crawling activity, synapse excitability, postsynaptic response, and anterograde Wnt/Wingless signaling, all of which modulate NMJ growth through LanA and ??. Our data indicate that synaptic activities down-regulate levels of the retrograde signal LanA to promote NMJ growth.

    View details for DOI 10.1073/pnas.1206416109

    View details for Web of Science ID 000311147800076

    View details for PubMedID 23054837

  • DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity CELL DEATH AND DIFFERENTIATION Wu, P., Tsai, P., Chen, G., Chou, H., Huang, Y., Chen, Y., Lin, M., KIMCHI, A., Chien, C., Chen, R. 2011; 18 (9): 1507-1520


    Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer's disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. In this study, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1/2. Accordingly, DAPK(-/-) mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well-characterized Drosophila model of tauopathy, we show that DAPK exerts an effect in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together, our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology.

    View details for DOI 10.1038/cdd.2011.2

    View details for Web of Science ID 000293998100014

    View details for PubMedID 21311567

  • LRRK2 Parkinson's disease: from animal models to cellular mechanisms REVIEWS IN THE NEUROSCIENCES Lin, C., Tsai, P., Wu, R., Chien, C. 2011; 22 (4): 411-418


    Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) play a major role in the development of Parkinson's disease. The most frequently defined mutations of LRRK2 are located in the central catalytic region of the LRRK2 protein, suggesting that dysregulations of its enzymatic activities contribute to PD pathogenesis. Herein, we review recent progress in research concerning how LRRK2 mutations affect cellular pathways and lead to neuronal degeneration. We also summarize recent evidence revealing the endogenous function of LRRK2 protein within cells. These concepts can be used to further understand disease pathophysiology and serve as a platform to develop therapeutic strategies for the treatment of Parkinson's disease.

    View details for DOI 10.1515/RNS.2011.036

    View details for Web of Science ID 000300084600003

    View details for PubMedID 21679126

  • LRRK2 G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3 beta JOURNAL OF NEUROSCIENCE Lin, C., Tsai, P., Wu, R., Chien, C. 2010; 30 (39): 13138-13149


    Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila dendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by the Drosophila glycogen synthase kinase 3? homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration.

    View details for DOI 10.1523/JNEUROSCI.1737-10.2010

    View details for Web of Science ID 000282571800025

    View details for PubMedID 20881132

  • Fak56 functions downstream of integrin alphaPS3betanu and suppresses MAPK activation in neuromuscular junction growth NEURAL DEVELOPMENT Tsai, P., Kao, H., Grabbe, C., Lee, Y., Ghose, A., Lai, T., Peng, K., Van Vactor, D., Palmer, R. H., Chen, R., Yeh, S., Chien, C. 2008; 3


    Focal adhesion kinase (FAK) functions in cell migration and signaling through activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Neuronal function of FAK has been suggested to control axonal branching; however, the underlying mechanism in this process is not clear.We have generated mutants for the Drosophila FAK gene, Fak56. Null Fak56 mutants display overgrowth of larval neuromuscular junctions (NMJs). Localization of phospho-FAK and rescue experiments suggest that Fak56 is required in presynapses to restrict NMJ growth. Genetic analyses imply that FAK mediates the signaling pathway of the integrin alphaPS3betanu heterodimer and functions redundantly with Src. At NMJs, Fak56 downregulates ERK activity, as shown by diphospho-ERK accumulation in Fak56 mutants, and suppression of Fak56 mutant NMJ phenotypes by reducing ERK activity.We conclude that Fak56 is required to restrict NMJ growth during NMJ development. Fak56 mediates an extracellular signal through the integrin receptor. Unlike its conventional role in activating MAPK/ERK, Fak56 suppresses ERK activation in this process. These results suggest that Fak56 mediates a specific neuronal signaling pathway distinct from that in other cellular processes.

    View details for DOI 10.1186/1749-8104-3-26

    View details for Web of Science ID 000260872100001

    View details for PubMedID 18925939

  • F-box proteins: the key to protein degradation JOURNAL OF BIOMEDICAL SCIENCE Ho, M. S., Tsai, P. I., Chien, C. T. 2006; 13 (2): 181-191


    The eukaryotic protein degradation pathway involves the ubiquitin (Ub) modification of substrates targeted for degradation by the 26S proteasome. The addition of Ub, a process called ubiquitination, is mediated by enzymes including the E3 Ub ligases which transfer the Ub to targeted substrates. A major type of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four major components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein. The F-box component of the SCF machineries is responsible for recognizing different substrates for ubiquitination. Interaction with components of the SCF complex is mediated through the F-box motif of the F-box protein while it associates with phosphorylated substrates through its second protein-protein interaction motif such as Trp-Asp (WD) repeats or leucine-rich repeats (LRRs). By targeting diverse substrates, F-box proteins exert controls over stability of proteins and regulate the mechanisms for a wide-range of cellular processes. Here we discuss the importance of F-box proteins by providing a general overview and examples of how F-box proteins function in various cellular settings such as tissue development, cell proliferation, and cell death, in the modeling organism Drosophila.

    View details for DOI 10.1007/s11373-005-9058-2

    View details for Web of Science ID 000236380800003

    View details for PubMedID 16463014

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