The long-term objective of this project is to characterize the molecular machinery responsible for eliminating misfolded, neurotoxic proteins so that they may be exploited for therapeutic intervention for neurodegenerative diseases such as spinobulbar muscular atrophy (SBMA). SBMA is a hereditary disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. SBMA is caused by trinucleotide (CAG) repeat expansion in the first exon of the androgen receptor gene leading to polyglutamine expansion in AR protein. Like other polyglutamine diseases, SBMA is characterized by accumulation of misfolded protein aggregates in degenerating neurons. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with intrinsic polyubiquitin-binding activity. We recently determined that over-expression of HDAC6 rescues degeneration in SBMA flies, flies with proteasome mutations, and other fly models of neurodegenerative disease. HDAC6 rescues degeneration by facilitating the degradation of aberrant, ubiquitinated protein by the autophagy-lysosomal system. In this application, we will (1) test specific hypotheses regarding the molecular mechanism whereby HDAC6 facilitates autophagic degradation of aberrant protein, (2) determine the therapeutic potential of HDAC6 in mammals, and (3) use the power of fly genetics to gain unanticipated insights into the role of HDAC6 in cellular management of misfolded protein stress.
Histone deacetylase 6 contributes to elimination of misfolded proteins from neurons and protects against neurodegeneration. It is not known how HDAC6 functions. This application seeks to understand the mechanism of HDAC6 function so that it may be exploited for therapeutics development.
|Alami, Nael H; Smith, Rebecca B; Carrasco, Monica A et al. (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536-543|
|Kim, Nam Chul; Tresse, Emilie; Kolaitis, Regina-Maria et al. (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78:65-80|
|Usenovic, Marija; Tresse, Emilie; Mazzulli, Joseph R et al. (2012) Deficiency of ATP13A2 leads to lysosomal dysfunction, ?-synuclein accumulation, and neurotoxicity. J Neurosci 32:4240-6|
|Mammen, Andrew L; Mahoney, James A; St Germain, Amanda et al. (2011) A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells. PLoS One 6:e28861|
|Batlevi, Yakup; Martin, Damali N; Pandey, Udai Bhan et al. (2010) Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila. Proc Natl Acad Sci U S A 107:742-7|
|Tresse, Emilie; Salomons, Florian A; Vesa, Jouni et al. (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6:217-27|
|La Spada, Albert R; Taylor, J Paul (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247-58|
|Freibaum, Brian D; Chitta, Raghu K; High, Anthony A et al. (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9:1104-20|
|Nedelsky, Natalia B; Todd, Peter K; Taylor, J Paul (2008) Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta 1782:691-9|