The La Spada Lab

at UC Irvine

Recent Publications

  1. Matthews I, Birnbaum A, Gromova A, Huang AW, Liu K, Liu EA, Coutinho K, McGraw M, Patterson DC, Banks MT, Nobles AC, Nguyen N, Merrihew GE, Wang L, Baeuerle E, Fernandez E, Musi N, MacCoss MJ, Miranda HC, La Spada AR & Cortes CJ. Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease. Cell Rep 42, 113436 (2023).

  2. Arnold FJ, Nguyen AD, Bedlack RS, Bennett CL & La Spada AR. Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave. Neurobiol Dis 184, 106218 (2023).Bennett CL, Dastidar S, Arnold FJ, McKinstry SU, Stockford C, Freibaum BD, Sopher BL, Wu M, Seidner G, Joiner W, Taylor JP, West RJH & La Spada AR. Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity. Acta Neuropathol Commun 11, 164 (2023).
  3. Gromova A, Cha B, Robinson EM, Strickland LM, Nguyen N, ElMallah MK, Cortes CJ & La Spada AR. X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease. Acta Neuropathol Commun 11, 90 (2023).
  4. Arnold FJ, Burns M, Chiu Y, Carvalho J, Nguyen AD, Ralph PC, La Spada AR & Bennett CL. Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice. Neurobiol Aging 126, 44-57 (2023).
  5. Cui Y*, Arnold FJ*, Peng F, Wang D, Li JS, Michels S, Wagner EJ, La Spada AR* & Li W*. Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders. Nat Commun 14, 583 (2023). *Co-corresponding authors.
  6. Campisi L, Chizari S, Ho JSY, Gromova A, Arnold FJ, Mosca L, Mei X, Fstkchyan Y, Torre D, Beharry C, Garcia-Forn M, Jiménez-Alcázar M, Korobeynikov VA, Prazich J, Fayad ZA, Seldin MM, De Rubeis S, Bennett CL, Ostrow LW, Lunetta C, Squatrito M, Byun M, Shneider NA, Jiang N, La Spada AR* & Marazzi I*. Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4. Nature 606, 945-952 (2022). *Co-corresponding authors.
  7. Bennett CL & La Spada AR. SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease. Mol Genet Genomic Med 9, e1745 (2021).
  8. Switonski PM, Delaney JR, Bartelt LC, Niu C, Ramos-Zapatero M, Spann NJ, Alaghatta A, Chen T, Griffin EN, Bapat J, Sopher BL & La Spada AR. Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7. Cell Rep 37, 110062 (2021).
  9. Dastidar SG, Pham MT, Mitchell MB, Yeom SG, Jordan S, Chang A, Sopher BL & La Spada AR. 4E-BP1 Protects Neurons from Misfolded Protein Stress and Parkinson’s Disease Toxicity by Inducing the Mitochondrial Unfolded Protein Response. J Neurosci 40, 8734-8745 (2020).
  10. Gromova A & La Spada AR. Harmony Lost: Cell-Cell Communication at the Neuromuscular Junction in Motor Neuron Disease. Trends Neurosci 43, 709-724 (2020).
  11. Bennett CL, Sopher BL & La Spada AR. Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly. Heliyon 6, e04165 (2020).
  12. Stoyas CA, Bushart DD, Switonski PM, Ward JM, Alaghatta A, Tang MB, Niu C, Wadhwa M, Huang H, Savchenko A, Gariani K, Xie F, Delaney JR, Gaasterland T, Auwerx J, Shakkottai VG & La Spada AR. Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7. Neuron 105, 630-644.e639 (2020).

Select Publications

  1. 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, 77-79 (1991).
  2. 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. Nat Genet 2, 301-304 (1992).
  3. 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, Ptácek LJ & Chen S. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31, 913-927 (2001). (Cover story)
  4. 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, 1904-1906 (2002). ^Co-first authors.
  5. 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. J Neurosci 22, 4897-4905 (2002). (Cover story)
  6. Sopher BL, Thomas PS, Jr., 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 VEGF164 in the motor neuron degeneration. Neuron 41, 687-699 (2004).
  7. Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT, La Spada AR* & Roeder RG*. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci U S A 102, 8472-8477 (2005). *Co-corresponding authors.
  8. 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). (Cover feature)
  9. 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 S, Sweet IR, Schwartz MW & La Spada AR. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4, 349-362 (2006). (Cover story)
  10. Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, Axford MM, Cleary JD, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE & La Spada AR. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet 4, e1000257 (2008).
  11. Chakrabarti L, Zahra R, Jackson SM, Kazemi-Esfarjani P, Sopher BL, Mason AG, Toneff T, Ryu S, Shaffer S, Kansy JW, Eng J, Merrihew G, MacCoss MJ, Murphy A, Goodlett DR, Hook V, Bennett CL, Pallanck LJ & La Spada AR. Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics. Neuron 66, 835-847 (2010).
  12. Furrer SA, Mohanachandran MS, Waldherr SM, Chang C, Damian VA, Sopher BL, Garden GA & La Spada AR. Spinocerebellar ataxia type 7 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, 16269-16278 (2011). (Cover story)
  13. Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E & La Spada AR. PGC-1α rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 4, 142ra197 (2012). (Selected by DISCOVER magazine as one of the top 100 scientific advances for 2012.)
  14. Cortes CJ, Ling SC, Guo LT, Hung G, Tsunemi T, Ly L, Tokunaga S, Lopez E, Sopher BL, Bennett CF, Shelton GD, Cleveland DW & La Spada AR. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 82, 295-307 (2014).
  15. Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, Ivanov N, Sopher BL, Carromeu C, Muotri AR, Garden GA & La Spada AR. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 17, 1180-1189 (2014).
  16. Dubinsky AN, Dastidar SG, Hsu CL, Zahra R, Djakovic SN, Duarte S, Esau CC, Spencer B, Ashe TD, Fischer KM, MacKenna DA, Sopher BL, Masliah E, Gaasterland T, Chau BN, Pereira de Almeida L, Morrison BE & La Spada AR. Let-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy. Cell Metab 20, 626-638 (2014).
  17. Tsai S, Sitzmann JM, Dastidar SG, Rodriguez AA, Vu SL, McDonald CE, Academia EC, O’Leary MN, Ashe TD, La Spada AR* & Kennedy BK*. Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. J Clin Invest 125, 2952-2964 (2015). *Co-corresponding authors.
  18. Dickey AS, Pineda VV, Tsunemi T, Liu PP, Miranda HC, Gilmore-Hall SK, Lomas N, Sampat KR, Buttgereit A, Torres MJ, Flores AL, Arreola M, Arbez N, Akimov SS, Gaasterland T, Lazarowski ER, Ross CA, Yeo GW, Sopher BL, Magnuson GK, Pinkerton AB, Masliah E & La Spada AR. PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med 22, 37-45 (2016). (Cover story)
  19. Dickey AS, Sanchez DN, Arreola M, Sampat KR, Fan W, Arbez N, Akimov S, Van Kanegan MJ, Ohnishi K, Gilmore-Hall SK, Flores AL, Nguyen JM, Lomas N, Hsu CL, Lo DC, Ross CA, Masliah E, Evans RM & La Spada AR. PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med 9 (2017).
  20. Mason AG, Garza RM, McCormick MA, Patel B, Kennedy BK, Pillus L & La Spada AR. The replicative lifespan-extending deletion of SGF73 results in altered ribosomal gene expression in yeast. Aging Cell 16, 785-796 (2017).
  21. Badders NM, Korff A, Miranda HC, Vuppala PK, Smith RB, Winborn BJ, Quemin ER, Sopher BL, Dearman J, Messing J, Kim NC, Moore J, Freibaum BD, Kanagaraj AP, Fan B, Tillman H, Chen PC, Wang Y, Freeman BB, III, Li Y, Kim HJ, La Spada AR & Taylor JP. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat Med 24, 427-437 (2018).
  22. Bennett CL, Dastidar SG, Ling SC, Malik B, Ashe T, Wadhwa M, Miller DB, Lee C, Mitchell MB, van Es MA, Grunseich C, Chen Y, Sopher BL, Greensmith L, Cleveland DW & La Spada AR. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. Acta Neuropathol 136, 425-443 (2018).
  23. Hsu CL, Lee EX, Gordon KL, Paz EA, Shen WC, Ohnishi K, Meisenhelder J, Hunter T & La Spada AR. MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB. Nat Commun 9, 942 (2018).
  24. Niu C, Prakash TP, Kim A, Quach JL, Huryn LA, Yang Y, Lopez E, Jazayeri A, Hung G, Sopher BL, Brooks BP, Swayze EE, Bennett CF & La Spada AR. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med 10 (2018).
  25. Gilmore-Hall S, Kuo J, Ward JM, Zahra R, Morrison RS, Perkins G & La Spada AR. CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice. J Cell Biol 218, 206-219 (2019).
  26. Ward JM, Stoyas CA, Switonski PM, Ichou F, Fan W, Collins B, Wall CE, Adanyeguh I, Niu C, Sopher BL, Kinoshita C, Morrison RS, Durr A, Muotri AR, Evans RM, Mochel F & La Spada AR. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease. Cell Rep 26, 1189-1202.e1186 (2019).