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Albert La Spada

Albert La Spada, MD, PhD

Professor and Chief, Division of Genetics in Department of Pediatrics
Professor, Cellular and Molecular Medicine

Contact Information

UC San Diego
9500 Gilman Dr. #0642
La Jolla, CA 92093

Office: 858-246-0148
Email: alaspada@ucsd.edu
Lab website:
http://laspadalab.ucsd.edu/Pages/default.aspx




Cellular and molecular mechanisms of neurodegenerative disease

In the La Spada laboratory, we apply the tools of molecular genetics, neuroscience, and functional genomics to understand the mechanisms of neurodegenerative disease. Within the last decade, it has become clear that a key question in the neurodegenerative disease field is the selective vulnerability of different neuronal populations in the various diseases. Inherited disorders such as Huntington's disease are characterized by widespread expression of a mutant gene product throughout the central nervous system but display well circumscribed patterns of neuronal dysfunction and demise. This theme is also apparent in genetic examples of common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and prion disease.

My lab primarily studies the molecular basis of the CAG / polyglutamine repeat diseases of which there are nine: Huntington's disease, X-linked spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and six forms of spinocerebellar ataxia. As the patterns of expression of the different disease genes are widespread throughout the neuraxis, the CAG / polyglutamine diseases represent an excellent example of neuronal selectivity. Thus, insights into the basis of selective neurodegeneration in these disorders may be relevant to understanding this phenomenon in a wide range of neurological disease processes. We have found that transcription dysregulation and activation of apoptosis and autophagy pathways are important in these diseases. In other studies, we have learned that protease function and proteolytic cleavage may be important. Our goal is to delineate the molecular and cellular pathways by which neurons become dysfunctional and use this knowledge to devise rational therapies for this class of diseases.

La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. (1991). Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352: 77-79

La Spada AR, Fu Y-H, Sopher BL, Libby RA, Wang X, Li LY, Einum DD, Huang J, Possin D, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptacek LJ, Chen S. (2001). Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31: 913-927 (Cover story)

La Spada AR^, Fernandez-Gonzalez A^, Treadaway J, Higdon JC, Harris BS, Sidman RL, Morgan JI, Zuo J. (2002). Purkinje cell degeneration (pcd) mouse phenotypes caused by mutations in the nerve regeneration-associated gene, Nna1. Science 295: 1904-1906 [^ = co-first authors]

Garden GA, Libby RT, Fu Y-H, 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. (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 (Cover story)

Sopher BL, Thomas PS, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM & La Spada AR. (2004). Androgen Receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF expression alteration in SBMA motor neuron degeneration. Neuron 41: 687-699

Thomas PS, Fraley GS, Damien V, Holm IE, Woodke LB, Zapata F, Sopher BL, Plymate SR & La Spada AR. (2006). Loss of endogenous AR 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. (Cover story)

Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, Guyenet SJ, Deller T, Westrum LE, Sopher BL & La Spada AR. (2006). Bergmann glia expression of polyglutamine-expanded ataxin-7 produces Purkinje cell degeneration and implicates glial-induced impairment of glutamate transport in SCA7. Nat Neurosci 9: 1302-1311 (Highlighted on cover)

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. (2006). Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1α transcription interference in Huntington’s disease neurodegeneration. Cell Metab 4: 349-362 (Cover story)

Young JE, Gouw L, Propp S, Lin A, Hermel E, Logvinova A, Chen SF, Bredesen DE, Sopher BL, Chen S, Ptacek LJ, Truant R, Fu Y-H, La Spada AR & Ellerby LM. (2007). Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation. J Biol Chem 282: 30150-30160

Libby RT, Hagerman K, Pineda VV, Lau R, Cho DH, Cleary JD, Baccam S, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE & La Spada AR. (2008). CTCF binding cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genetics 4: e1000257

Young JE, Martinez RA & La Spada AR. (2009). Nutrient deprivation induces neuronal autophagy, and implicates reduced insulin signaling in neuroprotective autophagy activation. J Biol Chem 284: 2363-2373 (Cover story)

Young JE*, Garden GA*, Taylor JP, Martinez RA, Tanaka F, Sandoval CM, Smith AC, Sopher BL, Ellerby LM, Morrison RS, Fischbeck KH & La Spada AR. (2009). Polyglutamine-expanded androgen receptor activates a Bax-dependent neuronal apoptotic cascade mediated by DP5/Hrk. J Neurosci 29: 1987-1997

La Spada AR & Taylor JP. (2010). Repeat expansion disease: Progress and puzzles in disease pathogenesis. Nature Rev Genet 11: 247-258

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. (2010). Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration (pcd) mice reveals a role for Nna proteins in neuronal bioenergetics. Neuron 66: 835-845

Batlevi Y & La Spada AR. (2011). Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiology of Disease 43: 46-51

Malik B, Nirmalananthan N, Bilsland LG, La Spada AR, Hanna MG, Schiavo G, Gallo JM & Greensmith L. (2011). Absence of disturbed axonal transport in Spinal and Bulbar Muscular Atrophy: implications for disease pathogenesis and therapeutic targets. Human Molecular Genetics 20: 1776-1786

Wilburn B, Rudnicki DD, Zhao J, Sopher BL, Osmand A, La Spada AR, Margolis RL, Sun YE & Yang XW. (2011). Bidirectional CUG/CAG transcripts and toxic polyglutamine-mediated CBP transcriptional dysregulation in Huntington’s Disease Like-2 (HDL-2) mice. Neuron 70: 427-440

Sopher BL, Ladd PD, Pineda VV, Libby RT, Sunkin SM, Hurley JB, Thienes CP, Terry Gaasterland T, Filippova GN& La Spada AR. (2011). CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense non-coding RNA. Neuron 70: 1071-1084

Furrer SA, Mohanachandan MS, Waldherr SM, Chang C, Damian VA, Sopher BL, Garden GA & La Spada AR. (2011). 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. Journal of Neuroscience 31: 16269-16278 (Cover story)

Tsunemi T, Soriano KR, Morrison BE, Au J, Vázquez Roque RA, Lazarowski ER, Damian VA, Masliah E & La Spada AR. (2012). PGC-1a rescues Huntington’s disease by preventing oxidative stress and promoting TFEB function. Science Translational Medicine 4, 142ra97

Furrer SA, Waldherr SM, Mohanachandan MS, Baughn TD, Nguyen KT, Sopher BL, Damian VA, Garden GA & La Spada AR. (2013). Reduction of mutant ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7. Human Molecular Genetics 22: 890 – 903

Cortes CJ, Ling S-C, Guo LT, Hung G, Tsunemi T, Ly L, Lopez E, Sopher BL, Bennett CF, Shelton GD, Cleveland DW & La Spada AR. (2014). Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in Spinal & Bulbar Muscular Atrophy. Neuron 82: 295-307

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. (2014). Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nature Neuroscience 17: 1180-1189

Dubinsky AN, Dastidar SG, Zahra R, Hsu CL, Djakovic S, Esau CC, Spencer B, Ashe TD, Fischer KM, MacKenna DA, Sopher BL, Masliah E, Gaasterland T, Chau NB, Morrison BE & La Spada AR. (2014). Let-7coordinately suppresses components of the amino acid sensing pathway to induce autophagy. Cell Metabolism20: 626-638