Identify molecular mechanisms of neurodegeneration in Huntington’s disease.
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
Diane Mao, MD, Lab Manager
Yanchun Pan, MS, Staff Scientist
Noman Bin Abid, PhD, Postdoctoral Fellow
Maryam Borhani-Haghighi, PhD, Postdoctoral Fellow
Andrew Speidell, PhD, Postdoctoral Fellow
Linjian Zhu, Lab Technician
Natalie Muldowney, Undergraduate Student
Sophie Laye, Undergraduate Student
Former Lab Members
Postdoctoral Fellows, Visiting Scientists
Takuji Daito, PhD, DVM, Hokkaido University, Japan
Qi Li, MD, Tongji Medical College, Huazhong University of Science and Technology in China
Santhi Pondugula, PhD, University of Florida
JaeWook Hyeon, PhD
Yong Hee (William) Chung
Ying (Selina) Zhu, University of Pennsylvania School of Dental Medicine
Fatima Al-Hanoosh, the PhD program in Biomedical Engineering at the University of Miami
Select Peer-Reviewed Publications
Mahlokozera T, Patel B, Chen H, Desouza P, Qu X, Mao DD, Hafez D, Yang W, Taiwo R, Paturu M, Salehi A, GujarA, Dunn GP, Mosammaparast N, Petti AA, Yano H, and Kim AH. Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma. Nat Commun 2021, 12:6321. PubMed PMID: 34732716.
Salehi A, Paturu MR, Patel B, Cain MD, Mahlokozera T, Yang AB, Lin TH, Leuthardt EC, Yano H, Song SK, Klein RS, Schmidt R, Kim AH. Therapeutic enhancement of blood-brain and blood-tumor barrier permeability by laser interstitial thermal therapy. Neurooncol Adv. Jun 2020. vdaa071, doi:10.1093/noajnl/vdaa071. PubMed PMID: 32666049
Pan Y, Zhu Y, Yang W, Tycksen E, Liu S, Palucki J, Zhu L, Sasaki Yo, Sharma MK, Kim AH, Zhang B, and Yano H. The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity. J Biol Chem 2018, 293(30):11850-11866. PubMed PMID: 29891550
Gujar AD, Le S, Mao DD, Dadey DY, Turski A, Sasaki Y, Aum D, Luo J, Dahiya S, Yuan L, Rich KM, Milbrandt J, Hallahan DE, Yano H, Tran DD, Kim AH. An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proc Natl Acad Sci U S A. 2016, 113(51):E8247-E8256. PubMed PMID: 27930300
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. PubMed PMID: 27516062
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, 11:1809-1821. PubMed PMID: 26074073
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. PubMed PMID: 24836077
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, 31:14496-14507. PubMed PMID: 21994366
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. PubMed PMID: 19940174
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, 40:1474-1481. PubMed PMID: 19246713
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, 9:1009-1018. PubMed PMID: 16819522
Yano H and Chao MV. Biochemical characterization of intracellular membrane compartments bearing the Trk neurotrophin receptors. Neurochemical Res 2005, 30:767-777. PubMed PMID: 16187212
Yano H and Chao MV. Mechanisms of neurotrophin receptor vesicular transport. Review, J Neurobiology 2004, 58:244-257. PubMed PMID: 14704956.