University of Washington
Department of Laboratory Medicine
NW 120 Health Sciences Building
Seattle, WA 98195-7110
Phone: (206) 598-2138
FAX: (206) 598-6189
In my laboratory, we apply the tools of molecular genetics and functional genomics to understand the mechanisms of neurological disease. In 1991, a novel type of genetic mutation known as a trinucleotide repeat expansion was discovered. At this time, it appears that 9 trinucleotide repeat diseases are caused by the expansion of a tract of glutamine residues within proteins that are unrelated to one another. We have focused our research efforts on two of these polyglutamine repeat diseases spinocerebellar ataxia type 7 (SCA7) and spinal & bulbar muscular atrophy (SBMA). An important question that we seek to answer is why do specific neurons die in each of these diseases, although the patterns of expression of the different disease genes are widespread and overlapping throughout the neuraxis. Recent emphasis has been placed upon modeling the retinal and neural degeneration in SCA7, understanding its mechanism, and trying to develop therapies to reverse it. In the case of SBMA, a lower motor neuron disease caused by polyglutamine repeat expansions in the androgen receptor (AR), we are trying to understand why motor neurons are exquisitely sensitive to glutamine tract expansions in AR by developing a variety of in vitro and in vivo models. Transcriptional dysregulation and the role of apoptotic activation are among the hypotheses that we are investigating.
An enigmatic phenomenon observed in the trinucleotide repeat diseases is genetic instability. Once triplet repeats reach a pathogenic size, they change in length when transmitted through the germline and during somatic cell division. We have launched a variety of studies aimed at determining the cis- and trans-acting factors that underlie the repeat instability process.
Another interest in my laboratory is the molecular basis of Parkinson's disease (PD). Our work on PD has focused upon the role of the synuclein proteins in causing neurodegeneration. Our interest in PD stems from the fact that like the polyglutamine repeat diseases, PD is characterized by the process of protein aggregation. The generation of peptide or protein aggregates in a variety of neurodegenerative diseases is a common theme in the study of neurological disorders. Our work on the polyglutamine repeat diseasesand on PD is intended to address why neurons share a propensity for aggregate formation and what the protein aggregation process can tell us about neuronal dysfunction and neuron cell death.
Investigator: Dr. La Spada is an Associate Professor of Laboratory Medicine, Medicine (Medical Genetics), and Neurology.
Weydt P*, Pineda VV*, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet SF, Sweet IR, Schwartz MW, La Spada AR. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1 alpha in Huntington’s disease neurodegeneration. Cell Metab 4: 349-362, 2006. (Cover Story)
Fan Y, Limprasert P, Murray IV, Smith AC, Lee VM, Trojanowski JQ, Sopher BL, La Spada AR. Beta- synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression. Hum Mol Genet 15:3002-3011, 2006.
Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, Guyenet SJ, Deller T, Westrum LE, Sopher BL, La Spada AR. Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 9: 1302-1311, 2006.
Thomas PS, Fraley GS, Damian V, Holm IE, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada AR. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet 15: 2225-2228, 2006. (Cover Story)
Taylor J, Grote SK, Xia J, Vandelft M, Graczyk J, Ellerby LM, La Spada AR, Truant R. Ataxin-7 nuclear export inhibition by direct cleavage of the ataxin-7 NES. J Biol Chem 281: 2730-2739, 2006.
Sopher BL and La Spada AR. Efficient recombination-based methods for bacterial artificial chromosome fusion and mutagenesis. Gene 371: 136-143, 2006.
Chakrabarti L, Martinez RA, Neal JT, Miles M, Huang J, Possin DE, Smith AC, Sopher BL, La Spada AR. The purkinje cell degeneration 5J allele mutation is a single amino acid insertion that destabilizes the Nna1 protein. Mammal Genome 17: 103-110, 2006. (Cover Story)
Palhan VB, Chen S, Peng G, Tjernberg A, Chait BT, Gamper AM, Fan Y, La Spada AR^, Roeder RG^. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration in a dominant negative manner. Proc Natl Acad Sci USA 102: 8472-8477, 2005 [^ co-corresponding authors].
Jackson S, Whitworth A, Greene JC, Baccam SL, Libby RT, Pallanck LJ, La Spada AR. A SCA7 CAG/CTG repeat expansion is stable in Drosophila melanogaster despite modulation of genomic context and gene dosage. Gene 347: 35-41, 2005.
Ohtake H*, Limprasert P*, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT, Tsuang DW, Murray IVJ, Lee VM-Y, Trojanowski JQ, Ishikawa A, Idezuka J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji S, La Spada AR. Beta-synuclein gene alterations in Dementia with Lewy Bodies. Neurology 63: 805-811, 2004.
Sopher BL, Thomas PS, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR. Androgen Receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF expression alteration in SBMA motor neuron degeneration. Neuron 41: 687-699, 2004.
Chen S, Peng G-H, Wang X, Smith AC, Grote SK, Sopher BL, La Spada AR. Interference of CRX-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization. Hum Mol Genet 13: 53-67, 2004. (Cover Story)
La Spada AR and Taylor JP. Polyglutamines placed into context. Neuron. 38(5): 681-4, 2003.
Libby RT, Monckton DG, Fu YH, Martinez RA, McAbney JP, Lau R, Einum DD, Nichol K, Ware CB, Ptacek LJ, Pearson CE, La Spada AR. Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice. Human Molecular Genetics. 12(1): 41-50, 2003.
Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, Smith AC, Martinez RA, Fine GC, Grote SK, Ware CB, Einum DD, Morrison RS, Ptacek LJ, Sopher BL, La Spada AR. Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 22(12): 4897-905, 2002.
Fernandez-Gonzalez A, La Spada AR, Treadaway J, Higdon JC, Harris BS, Sidman RL, Morgan JI, Zuo J. Purkinje cell degeneration (pcd) phenotypes caused by mutations in the axotomy-induced gene, Nna1. Science. 295(5561): 1904-6, 2002.
La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptacek LJ, Chen S. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron. 31(6): 913-27, 2001.
Sopher BL, Myrick SB, Hong JY, Smith AC, La Spada AR. In vivo expansion of trinucleotide repeats yields plasmid and YAC constructs for targeting and transgenesis. Gene. 261(2): 383-90, 2000.
Fernandez M, McClain ME, Martinez RA, Snow K, Lipe H, Ravits J, Bird TD, La Spada AR. Late-onset SCA2: 33 CAG repeats are sufficient to cause disease. Neurology. 55(4): 569-72, 2000.
La Spada AR, Peterson KR, Meadows SA, McClain ME, Jeng G, Chmelar RS, Haugen HA, Chen K, Singer MJ, Moore D, Trask BJ, Fischbeck KH, Clegg CH, McKnight GS. Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability. Human Molecular Genetics. 7(6): 959-67, 1998.
La Spada AR. Trinucleotide repeat instability: genetic features and molecular mechanisms. Brain Pathology. 7(3): 943-63, 1997.
La Spada AR, Clark AW. Inherited neurodegenerative disorders caused by CAG/polyglutamine tract expansions: symposium introduction. Brain Pathology. 7(3): 877-80, 1997.
La Spada AR, Sk alhegg BS, Henderson R, Schmer G, Pierce R, Chandler W. Brief report: fatal hemorrhage in a patient with an acquired inhibitor of human thrombin. New England Journal of Medicine. 333(8): 494-7, 1995.
La Spada AR, Paulson HL, Fischbeck KH. Trinucleotide repeat expansion in neurological disease. Annals of Neurology. 36(6): 814-22, 1994.
La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nature Genetics. 2(4): 301-4, 1992.
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 352(6330): 77-9, 1991.