Garden Laboratory

Lab Members

• Gwenn Garden
• Lisa Baldwin
• Travis Baughan
• Stephanie Furrer
• Stephanie Hopkins
• Manthini Mohonachandran
• K.T. Nguyen
• Galen Pizzorno
• Aurelio Silvestroni
• Bryce Sopher
• Min Spencer 

Contact Us

Garden Lab
University of Washington
1959 NE Pacific St
HSB K207, 209, 533
Department of Neurology
Seattle, WA 98195
Phone: K533 (206)

K209-(206)

Gwenn Garden, M.D, Ph.D
Phone: (206) 616-9402,
Fax: (206) 685-8100
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Garden Laboratory

Molecular Regulation of Microglia Behavior

Microglia, resident CNS immune cells, are activated in response to both acute and chronic neural injury. When microglia are activated, they may adopt a variety of responses including a neurotoxic response involving the release of inflammatory cytokines and neurotoxic substances or a neuroprotective response that includes the secretion of trophic factors and promotion of tissue repair. The molecular patterns that regulate which microglia response pattern will be dominant are not well understood. Our group has been examining the role of a number of pathways in modulating microglia behavior and response patterns. We have focused extensively on specific transcriptional regulators that are induced by oxidative stress as well as genes known to be involved in the pathogenesis of Alzheimer's disease and microRNAs with demonstrated roles in modulating the behavior of macrophages. The overarching goal of this research program is to identify potential therapeutic targets that could modify the inflammatory response to neural injury by promoting microglia to adopt the neuroprotective as opposed to neurotoxic pattern of response to neural injury.

Poly Glutamine Neurodegeneration

Huntington Disease

Huntington's Disease (HD) is an inherited neurodegenerative disease caused by autosomal dominant transmission of an expanded CAG repeat in the coding region of the huntingtin gene. HD leads to progressive neurodegeneration primarily in the basal ganglia and cortex. Patients develop progressive motor and cognitive dysfunction that eventually leads to early mortality. We employ a mouse model of HD in which the mutant human huntingtin gene has been knocked into the mouse locus. We are studying several hypotheses of disease pathogenesis including the role of the trophic factor insulin like growth factor -1 (IGF-1) and degeneration of axons and myelin in white matter structures of HD mice. We employ a variety of approaches including molecular characterization of IGF-1 signaling, transport and metabolism and light, fluorescent and transmission electron microscopy to study the pathology of white matter in HD mice.

Spinocerebellar Ataxia Type 7

Spinal Cerebellar Ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ataxin-7 gene. The main characteristics of the disorder include ataxia, retinal degeneration and atrophy of the cerebellum and associated brain stem structures. Our research on SCA7 is focused on experiments to evaluate hypothesis that polyglutamine expanded ataxin-7 results in an altered Purkinje cell (PC) environment within the cerebellum. This altered environment specifically affects neurons that are involved in generating postural tone and coordinated movements. The corollary to this hypothesis is that if some or all of the specific components of the altered environment can be corrected, neurological function may improve and neurodegeneration may be prevented in SCA7 patients. Using a conditional knockout model of SCA7, we have identified a number of key cellular players in the pathogenesis of neurodegeneration in SCA7. To further address the role of non-cell autonomous factors in SCA7 pathogenesis, we are evaluating the role of IGF-1 using similar approaches in SCA7 as in HD. We are also addressing a potential role for myelin pathology in SCA7 and have extensively evaluated the importance of specialized cerebellar glia known as Bergmann glia. We are developing approaches to evaluate transcriptional changes in specific cell types employing laser capture micro-dissection (LCM), fluorescence activated cell sorting (FACS), amplification from small quantity RNA samples and next generation sequencing approaches (RNA-seq).

Garden Laboratory

Publications

• Kaul M, Garden G and Lipton S. (2001) Pathways to Neuronal Injury and Apoptosis in HIV-Associated Dementia. Nature 410:988-994.
• Garden G, Budd S, Tsai E, Hanson L, Kaul M, De'Emillia D., Friedlander R, Yuan J, Masliah E and Lipton S. (2002) Caspase Cascades in Human Immunodeficiency Virus-Associated Neurodegeneration.  J. Neurosci. 22:4015-4024.
• Garden G, Libby R, Fu Y-H, Kinoshita Y, Huang J, Possin D, Smith A, Martinez R, Fine G, Grote S, Ware C, Einum D, Morrison R, Ptacek L, Sopher B and La Spada A (2002) Polyglutamine Expanded Ataxin-7 Promotes Non-Cell Autonomous Purkinje Cell Degeneration And Displays Proteolytic Cleavage In Ataxic Transgenic Mice.  J. Neurosci. 22:4897-4905 (Selected as Cover Article)
• Garden G. (2002) Microglia in Human Immunodeficiency Virus-Induced Neurodegeneration.  Glia  40:240-251.
• Morrison R, Kinoshita Y, Johnson M, Guo W and Garden G (2003) p53-dependent Cell Death Signaling in Neurons.  Neurochem Res.  28:15-27
• Hu S, Walker M, Czartoski T, Cheng A, Forghani B, Gilden D and Garden G (2004) Acyclovir-Responsive Brain Stem Disease Following the Ramsay Hunt syndrome.  J. Neurol. Sci., 217:111-113.
• Digicaylioglu, M, Garden G, Timberlake S, Fletcher L and Lipton S (2004) Acute Neuroprotective Synergy of Erythropoietin and Insulin-Like Growth Factor-1. Proc. Natl. Acad. Sci. 101(26):9855-60.
• Garden G, Guo W, Jayedev S, Tun C, Balcaitis S, Choi J, Montine T, Möller T and Morrison R (2004) HIV Associated Neurodegeneration Requires p53 in Neurons and Microglia. FASEB J. 18(7):U567-569. Full length version published on line at www.fasebj.org/cgi/content/abstract/04-1676fjev1.
• Garden G and Morrison R. (2005) The Multiple Roles of p53 in the Pathogenesis of HIV Associated Dementia. Biochem. Biophys. Res. Comm. 331(3):799-809.
• Takaya N, Yuan C, Chu G, Saam T, Underhill H, Cai J, Tran N, Polissar N, Isaac C, Ferguson M, Garden G, Cramer S, Maravilla K, Hashimoto B and Hatsukami T, (2006) Association Between Carotid Plaque Characteristics and Subsequent Ischemic Cerebrovascular Events: A Prospective Assessment with Magnetic Resonance Imaging.  Stroke 37:818-23.
• Garden G and Möller T. (2006) Microglia Biology in Health and Disease. J. Neuroimmun. Pharmacol. 1:127-137.
• Custer S, Garden G, Gill N, Libby R, Guyenet S, Westrum L, Sopher B, Laspada A. (2006) Bergmann glia expression of polyglutamine-expanded ataxin-7 produces Purkinje cell degeneration and implicates glial-induced impairment of glutamate transport in SCA7. Nature Neurosci. Oct 9(10):1302-11
• Saam T, Yuan C, Chu B, Takaya N, Underhill H, Cai J, Tran N, Polissar N, Neradilek B, Jarvik G, Isaac C, Garden G, Cramer S, Maravilla K, Hashimoto B and Hatsukami T. (2006) Predictors of Carotid Athersclerotic Plaque Progression as Measured by Noninvasive Magnetic Resonance Imaging. Atherosclerosis Sep 13: doi:10.1016
• Kinoshita Y, Uo T, Jayadev S, Garden G, Conrads T, Veenstra T and Morrison R. (2006) Potential Applications and Limitations of Proteomics in the Study of Neurological Disease. Archives of Neurol. 63:1692-1696.
• Tun C, Guo W, Nguyen H, Yun B, Libby R, Morrison R and Garden G. (2007). Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53 mediated down regulation of the X-linked inhibitor of apoptosis protein to induce apoptosis. J. Neurochem. 102:1206-1219.
• Jayadev S, Yun B, Nguyen H, Yokoo H, Morrison R and Garden G.  (2007) The Glial Response to CNS HIV Infection Includes p53 Activation and Increased Expression of p53 Target Genes. J. Neuro. Immun. Pharmacol. 2(4):359-70.
• Garden G and La Spada A (2008) Molecular Pathogenesis and Cellular Pathology of Spinocerebellar Ataxia Type 7 Neurodegeneration. The Cerebellum. 7(2):138-49. PMID: 17853090.
• Young J*, Garden G*, Martinez R, Tanaka F, Sandoval C, Smith N, Sopher B, Lin A, Fischbeck K, Ellerby L, Morrison R, Taylor J, and La Spada A, (2009) Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. J Neurosci. 29(7):1987-97. PMID: 19228953.  (*=Equal Contributions)
• Jayadev S and Garden G (2009) Host and Viral Factors Influencing the Pathogenesis of HIV Associated Neurocognitive Disorders. J. Neuroimmun. Pharmacol. 4(2):175-189, PMID:19345186.
• Klintworth H, Garden G and Xia Z (2009) Rotenone And Paraquat Do Not Directly Activate Microglia or Induce Inflammatory Cytokine Release. Neurosci Lett. 462(1):1-5. PMID: 19559752
• Chakrabarti L, Eng J, Gill N, Garden G and La Spada A (2009) Autophagy Activation and Enhanched Mitophagy Characterize the Purkinje Cells of pcd Mice Prior to Neuronal Death. Mol. Brain. 2(1):24. PMID: 19640278.
• Guyenet S, Furrer S, Damian V, Baughan T, La Spada A, Garden G (2010). A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia. J. Vis. Exp. http://www.jove.com/index/details.stp?id=1787, doi: 10.3791/1787. PMID: 20495529.
• Jayadev S, Case A, Nguyen H, Möller T, Morrison R and Garden G (2010) Presenilin 2 is the Predominant γ-secretase in Microglia and Modulates Cytokine Release. PLOS One. 5(12):e15743. PMID: 21206757.
• Jayadev S, Nessor N, Hopkins S, Myers S, Case A, Lee R, Seaburg L, Uo T, Murphy S, Morrison R and Garden G (2011) The Transcription Factor p53 Influences Microglia Activation Phenotype. Glia. 59(10):1402-13. PMID: 21598312.
• Furrer S, Mohanachandran M, Waldherr S, Chang C, Damian V, Sopher B, Garden G* and La Spada A* (2011) SCA7 Cerebellar Disease Requires The Coordinated Action Of Mutant Ataxin-7 In Neurons And Glia, And Displays Non-Cell Autonomous Bergmann Glia Degeneration. J Neurosci. 31(45):16269-78. PMID: 22072678. (*=Equal Contributions)
• Jebelli J, Hooper C, Garden G and Pocock J (2012) p53 in the CNS: emerging roles for Glia. Glia; 60 (4) 515-25. PMID: 22105777.
• Garden G and La Spada A. (2012) Intercellular (Mis)communication in Neurodegenerative Diseases. Neuron. 73(5):886-901.