The Yano Laboratory is in the Department of Neurological Surgery at Washington University School of Medicine and is affiliated with the Departments of Neurology and Genetics. Our laboratory aims to identify molecular mechanisms of neurodegeneration in neurological disorders, in particular, in Huntington’s disease (HD), a progressive and fatal neurodegenerative disease with no effective treatment to date. Using primary neuron and mouse models of the disease, we are trying to understand how selective neurons in the brain become dysfunctional and die in HD through various approaches, including molecular biology, cell biological, biochemistry, and genetics. Our ultimate goal is to discover new therapeutic strategies targeting disease-specific molecular changes to prevent neurodegeneration in human HD and potentially other neurodegenerative disorders.
The age-dependent dysfunction and progressive loss of selective neurons are key characteristics of neurodegenerative disorders, including Huntington’s disease (HD). HD is a devastating fatal neurodegenerative disease characterized by selective neuronal loss in the striatum and cortex due to an aberrant polyglutamine expansion in the huntingtin protein. Disease symptoms include abnormal body movements, cognitive decline, and psychiatric disorders. Despite intensive efforts to identify the molecular mechanisms of neuronal death in HD, no curative treatments are currently available. Our laboratory research interest is to understand at the molecular level how mutant huntingtin drives abnormal cellular changes, with a particular focus on transcriptional dysregulation and mitochondrial dysfunction, and how these changes lead to neuronal death and dysfunction.
Transcriptional dysregulation in Huntington’s disease
Altered gene expression in the brain is an early abnormality in the course of HD progression and is thought to play a central role in the pathogenesis of this disease. Emerging evidence suggests that epigenetic mechanisms, including DNA methylation and posttranslational modification of histones, which influence chromatin structure, play important roles in the transcriptional dysregulation observed in HD. Our underlying hypothesis is that epigenetic dysregulation of genes important for neuronal function and survival causes neuronal dysfunction and death in HD. The current objectives in our laboratory are 1) to identify critical transcripts altered in HD neurons using postmitotic neuronal culture and animal models of the disease, 2) to identify novel epigenetic mechanisms that drive key gene expression changes and subsequently cause neuronal dysfunction and death, and 3) to test the effect of pharmacological and genetic manipulation of disease-specific epigenetic pathways on the behavior and survival of HD transgenic mice, all with the aim of identifying potential therapies for human HD. Given that HD has psychiatric manifestations, including anxiety and depression, we are also interested in identifying treatments to ameliorate these symptoms through animal behavioral studies. To achieve these research objectives, we use a diverse set of techniques, including lentivirus-mediated gene expression and RNA interference, recently developed next-generation sequencing technology for genome-wide transcriptome and epigenome analyses, and high-throughput epigenetic-focused drug library screen using a primary neuron model of HD. Our long-term goal is to develop novel epigenetics-directed therapies to prevent or slow the progression of neurodegenerative disease.
Mitochondrial dysfunction in Huntington’s disease
In addition to transcriptional dysregulation, another important cellular alteration that is believed to be associated with neuronal loss in HD is mitochondrial dysfunction. However, the mechanisms driving mitochondrial dysfunction and neurodegeneration in HD remain largely unknown. We recently discovered a mechanism by which mutant huntingtin directly impairs mitochondrial protein import through an interaction with the TIM23 import machinery. We also demonstrated that defective TIM23-dependent protein import triggers mutant Htt-induced mitochondrial neuronal death. These findings suggest the intriguing possibility that restoration of mitochondrial protein import represents a novel therapeutic strategy for HD and other neurodegenerative diseases, which exhibit deficient mitochondrial protein import.
Hiroko Yano, PhD, Principal Investigator
JaeWook Hyeon, PhD, Post-doctoral Fellow
Diane Mao, MD, Lab Manager
Yanchun Pan, MS, Lab Technician
Linjian Zhu, Lab Technician
Manuel Panzardi, Undergraduate Student
Fatima Al-Hanoosh, Undergraduate Student
Former Lab Members
Takuji Daito, PhD, DVM, Hokkaido University, Japan
Qi Li, MD, Tongji Medical College, Huazhong University of Science and Technology in China
Rahul Kumar, PhD
Yong Hee (William) Chung
Ying (Selina) Zhu
Select Peer-Reviewed Publications
Yano H, Cong F, Birge RB, Goff SP, and Chao MV. Association of the Abl tyrosine kinase with the Trk nerve growth factor receptor. J Neurosci Res2000, 59:356-64.
Yano H, Lee FS, Kong H, Chuang J, Arevalo J, Perez P, Sung C, and Chao MV. Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor. J Neurosci 2001, 21:RC125.
Lou X*, Yano H*, Lee F, Chao MV, and Farquhar MG. (* The first two authors contributed equally to this manuscript.) GIPC and GAIP form a complex with TrkA: a putative link between G protein and receptor tyrosine kinase pathways. Mol Biol Cell 2001, 12:615-27.
Khursigara G, Bertin J, Yano H, Moffett H, DiStefano PS, and Chao MV. A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J Neurosci2001, 21:5854-63.
Kim AH, Yano H, Cho H, Meyer D, Monks B, Margolis B, Birnbaum M, Chao MV. Akt1 regulates a JNK scaffold during excitotoxic apoptosis. Neuron2002, 35:697-709.
Arevalo JC, Yano H, Teng KK, and Chao MV. A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J 2004, 23:2358-68.
Yano H and Chao MV. Biochemical characterization of intracellular membrane compartments bearing the Trk neurotrophin receptors. Neurochemical Res 2005, 30:767-77.
Taveggia C, Zanazzi G, Petrylak A, Yano H, Rosenbluth J, Einheber S, Xu X, Esper RM, Loeb JA, Shrager P, Chao MV, Falls DL, Role L, and Salzer JL. Neuregulin-1 Type III Determines the Ensheathment Fate of Axons. Neuron 2005, 47:681-94.
Arevalo JC, Pereira DB, Yano H, Teng KK, and Chao MV. Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. J Biol Chem 2006, 281:1001-7.
Yano H, Ninan I, Zhang H, Milner TA, Arancio O, and Chao MV. BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Nat Neurosci 2006, 9:1009-18.
Chen L, Tanriover G, Yano H, Friedlander R, Louvi A, Gunel M. Apoptotic functions of PDCD10/CCM3, the gene mutated in cerebral cavernous malformation 3. Stroke 2009, 40:1474-81.
Yano H, Torkin R, Martin LA, Chao MV, and Teng KK. Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing. J Neurosci 2009, 29:14790-14802.
Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, and Friedlander RM. The melatonin-MT1 receptor axis modulates mutant huntingtin-mediated toxicity. J Neurosci 2011, 31:14496-507.
Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, and Friedlander RM. Inhibition of mitochondrial protein import by mutant huntingtin. Nat Neurosci 2014, 17:822-831. PMCID: PMC4174557.
Mao DD, Gujar AD, Mahlokozera T, Chen I, Pan Y, Luo J, Brost T, Thompson EA, Turski A, Leuthardt EC, Dunn GP, Chicoine MR, Rich KM, Dowling JL, Zipfel GJ, Dacey RG, Achilefu S, Tran DD, Yano H, Kim AH. A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-Like Cells. Cell Rep 2015, 11:1809-21.
Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, Pondugula S, Swamidass, SJ, Wang T, Kim AH, Yano H. Inhibition of DNA methyltransferases blocks mutant huntingtin-induced neurotoxicity. Sci Rep 2016, 6:31022.
PanY, ZhuY, YangW, TycksenE, LiuS, Palucki J, ZhuL, Sasaki Yo, SharmaMK, Kim AH, ZhangB, and YanoH. The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity. J Biol Chem 2018, 293(30):11850-11866.
Review Articles and Book Chapters
Yano H. and Chao MV. Neurotrophin receptor structure and interactions. Pharm Acta Helv 2000, 74:253-60.
Yano H and Chao MV. Mechanisms of neurotrophin receptor vesicular transport. J Neurobiology 2004, 58:244-57.