Honors & Awards
Fellowship award of PDF, Parkinson' Disease Foundation (2014-2015)
Dean’s Postdoctoral Fellowship, Stanford University School of Medicine (2013-2014)
C B. Carringtong Memorial Award, Department of Pathology, Stanford University School of Medicine (2013)
Outstanding Graduate Student Research Scholarship, Tsinghua University, China (2009-2011)
National Scholarship First-class, Tsinghua University and Ministry of Education (China) (2004)
Wu-Shunde Couple Scholarship, Tsinghua University, China (2003)
Doctor of Philosophy, Tsinghua University (2010)
Bingwei Lu, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
mechanism of Parkinson's disease, Alzheimer's disease, and other rare genetic degenerative diseases.
Used to work on NBIA and metal induced neurodegeneration.
PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane
2015; 21 (1): 95-108
Mitochondria play essential roles in many aspects of biology, and their dysfunction has been linked to diverse diseases. Central to mitochondrial function is oxidative phosphorylation (OXPHOS), accomplished by respiratory chain complexes (RCCs) encoded by nuclear and mitochondrial genomes. How RCC biogenesis is regulated in metazoans is poorly understood. Here we show that Parkinson's disease (PD)-associated genes PINK1 and Parkin direct localized translation of certain nuclear-encoded RCC (nRCC) mRNAs. Translationally repressed nRCC mRNAs are localized in a PINK1/Tom20-dependent manner to mitochondrial outer membrane, where they are derepressed and activated by PINK1/Parkin through displacement of translation repressors, including Pumilio and Glorund/hnRNP-F, a Parkin substrate, and enhanced binding of activators such as eIF4G. Inhibiting the translation repressors rescued nRCC mRNA translation and neuromuscular-degeneration phenotypes of PINK1 mutant, whereas inhibiting eIF4G had opposite effects. Our results reveal previously unknown functions of PINK1/Parkin in RNA metabolism and suggest new approaches to mitochondrial restoration and disease intervention.
View details for DOI 10.1016/j.cmet.2014.12.007
View details for Web of Science ID 000347467900013
- RNA metabolism in the pathogenesis of Parkinson's disease BRAIN RESEARCH 2014; 1584: 105-115
Zinc Binding Directly Regulates Tau Toxicity Independent of Tau Hyperphosphorylation
2014; 8 (3): 831-842
Tau hyperphosphorylation is thought to underlie tauopathy. Working in a Drosophila tauopathy model expressing a human Tau mutant (hTauR406W, or Tau(∗)), we show that zinc contributes to the development of Tau toxicity through two independent actions: by increasing Tau phosphorylation and, more significantly, by directly binding to Tau. Elimination of zinc binding through amino acid substitution of Cys residues has a minimal effect on phosphorylation levels yet essentially eliminates Tau toxicity. The toxicity of the zinc-binding-deficient mutant Tau(∗) (Tau(∗)C2A) and overexpression of native Drosophila Tau, also lacking the corresponding zinc-binding Cys residues, are largely impervious to zinc concentration. Importantly, restoration of zinc-binding ability to Tau(∗) by introduction of a zinc-binding residue (His) into the original Cys positions restores zinc-responsive toxicities in proportion to zinc-binding affinities. These results indicate zinc binding is a substantial contributor to tauopathy and have implications for therapy development.
View details for DOI 10.1016/j.celrep.2014.06.047
View details for Web of Science ID 000341572200019
View details for PubMedID 25066125
hSOD1 Promotes Tau Phosphorylation and Toxicity in the Drosophila Model.
Journal of Alzheimer's disease : JAD
Tau hyperphosphorylation has been found in several neurodegenerative diseases such as Alzheimer's disease (AD), Down syndrome, and amyotrophic lateral sclerosis (ALS). However, factors affecting tau hyperphosphorylation are not yet clearly understood. SOD1, a Cu/Zn superoxide dismutase whose mutations can cause adult-onset ALS, is believed to be involved in the pathology of Down syndrome. In this work, the model organism Drosophila was used to study the possible link between hSOD1 and tau. Our results show that hSOD1, and to a higher degree hSOD1(A4V), can increase tau toxicity in Drosophila and exacerbate the corresponding neurodegeneration phenotype. The increased tau toxicity appears to be explainable by elevated tau phosphorylation. Tau(S2A), a tau mutant with impaired phosphorylation capabilities, does not respond to expression of hSOD1 and hSOD1(A4V). We suggest that increased SOD1 expression can lead to tau hyperphosphorylation, which might serve as an important contributing factor to the etiology of Down syndrome and SOD1-related ALS disease.
View details for DOI 10.3233/JAD-141608
View details for PubMedID 25524953
Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway
GENES & DEVELOPMENT
2013; 27 (24): 2642-2647
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
View details for DOI 10.1101/gad.225169.113
View details for Web of Science ID 000328892800003
Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance
GENES & DEVELOPMENT
2013; 27 (2): 157-162
Eukaryotes employ elaborate mitochondrial quality control (MQC) to maintain the function of the power-generating organelle. Parkinson's disease-associated PINK1 and Parkin actively participate in MQC. However, the signaling events involved are largely unknown. Here we show that mechanistic target of rapamycin 2 (mTORC2) and Tricornered (Trc) kinases act downstream from PINK1 to regulate MQC. Trc is phosphorylated in mTORC2-dependent and mTORC2-independent manners and is specifically localized to mitochondria in response to PINK1, which regulates mTORC2 through mitochondrial complex-I activity. Genetically, mTORC2 and Trc act upstream of Parkin. Thus, multiplex kinase signaling is acting between PINK1 and Parkin to regulate MQC, a process highly conserved in mammals.
View details for DOI 10.1101/gad.203406.112
View details for Web of Science ID 000314044800005
Mitochondrial release of the NADH dehydrogenase Ndi1 induces apoptosis in yeast
MOLECULAR BIOLOGY OF THE CELL
2012; 23 (22): 4373-4382
Saccharomyces cerevisiae NDI1 codes for the internal mitochondrial ubiquinone oxidoreductase, which transfers electrons from NADH to ubiquinone in the respiratory chain. Previously we found that Ndi1 is a yeast homologue of the protein apoptosis-inducing factor-homologous mitochondrion-associated inducer of death and displays potent proapoptotic activity. Here we show that S. cerevisiae NDI1 is involved in apoptosis induced by various stimuli tested, including H(2)O(2), Mn, and acetate acid, independent of Z-VAD-fmk (a caspase inhibitor) inhibition. Although Ndi1 also participates in respiration, its proapoptotic property is separable from the ubiquinone oxidoreductase activity. During apoptosis, the N-terminal of Ndi1 is cleaved off in the mitochondria, and this activated form then escapes out to execute its apoptotic function. The N-terminal cleavage appears to be essential for the manifestation of the full apoptotic activity, as the uncleaved form of Ndi1 exhibits much less growth-inhibitory activity. Our results thus indicate an important role of Ndi1 in the switch of life and death fates in yeast: during normal growth, Ndi1 assimilates electrons to the electron transport chain and initiates the respiration process to make ATP, whereas under stresses, it cleaves the toxicity-sequestering N-terminal cap, is released from the mitochondria, and becomes a cell killer.
View details for DOI 10.1091/mbc.E12-04-0281
View details for Web of Science ID 000314404700004
View details for PubMedID 22993213
Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production
NEUROBIOLOGY OF AGING
2012; 33 (1)
The neurotoxicity of aluminum (Al) - the most abundant metal element on earth - has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of ?-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.
View details for DOI 10.1016/j.neurobiolaging.2010.06.018
View details for Web of Science ID 000297934700031
View details for PubMedID 20674094
Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model
HUMAN MOLECULAR GENETICS
2009; 18 (19): 3659-3672
Pantothenate-Kinase-Associated-Neurodegeneration (PKAN) is a devastating disease, resulting from mutations in pantothenate kinase 2 (PANK2), one of the four human pantothenate kinase genes (PANK1-4). Interestingly, PanK2 appears to be the only mitochondria-targeted human PanK. It is unknown whether the mitochondria-targeted PanK is associated with any unique function, nor whether PKAN is due solely to the loss of pantothenate kinase activity. Drosophila PANK [fumble (fbl)] encodes several isoforms of pantothenate kinase products, one of which localizes to mitochondria and the others cytosol. fbl flies exhibit many characteristic features reminiscent of PKAN patients. Various forms of Drosophila fbl and human PANK2 were introduced into fbl flies to study their in vivo functions. Only mitochondria-targeted Fbl or human PanK2 was able to rescue fbl mutation, with the rescuing ability sensitive to the expression level of the transgene. Transgenic lines with low expression of normal Fbl or PanK2 displayed similar phenotypes as PANK2 mutant transgenic flies. These PanK2 mutants all showed reduced and phenotype severity-correlated in vitro pantothenate kinase activities. Amazingly, cytosolic PanK3 and PanK4 could mostly, but not fully, rescue fbl defects except the male sterility. Therefore, fbl appears to be the orthologue of human PANK2, and PanK2 is functionally more potent than PanK3 and PanK4 in vivo. We suggest that mitochondria-located pantothenate kinase is required to achieve the maximal enzymatic activity to fulfill the most challenging task such as maintaining male fertility and optimal neuronal functions, and PKAN features are mainly due to the reduction of the total cellular pantothenate kinase activity in the most susceptible regions.
View details for DOI 10.1093/hmg/ddp314
View details for Web of Science ID 000270707900012
View details for PubMedID 19602483
Dietary rescue of fumble - a Drosophila model for pantothenate-kinase-associated neurodegeneration
JOURNAL OF INHERITED METABOLIC DISEASE
2005; 28 (6): 1055-1064
Hallervorden-Spatz syndrome (HSS) is a devastating neurological disease, characterized by iron accumulation in the globus pallidus in the basal ganglia. Most HSS cases are caused by mutations in one of the four human pantothenate kinases (PANK2). This PANK2-caused subgroup of HSS is sometimes referred as PKAN (pantothenate-kinase-associated neurodegeneration). No effective treatment for PKAN or HSS is currently available. fumble, a Drosophila mutant that carries a mutation in Drosophila Pank, has many features similar to those of PKAN patients. In this study, we used fumble as a model to evaluate various compounds or nutritional products for their possible therapeutic efficacy. While no product was found to dramatically improve the symptoms, GKE (containing Ginkgo biloba extract and flavone) and vitamin E showed statistically significant beneficial effects. Our studies indicate that pantothenate is of limited value in alleviating fumble phenotypes and also suggest that some compounds might have deleterious effects.
View details for DOI 10.1007/s10545-005-0200-0
View details for Web of Science ID 000234907300028
View details for PubMedID 16435199