Recent published studies by our laboratory and others have shown that mutant huntingtin (htt)-mediated transcription dysregulation of PGC-11 disrupts expression of genes necessary for normal mitochondrial function and energy metabolism in the striatum. These findings led to a new understanding of the pathogenesis of mitochondrial dysfunction in Huntington's disease (HD), linking nuclear PGC-11 transcription interference with altered mitochondrial function. As a transcription co-activator, PGC-11 positively modulates several nuclear receptors, including the three PPAR's, termed 1, 3, and 4. Of these, PPAR4 is the most abundantly expressed subtype in the CNS, although its functional relevance in this tissue is yet to be defined. Based upon an unbiased screen for htt transcription factor interactors, we identified PPAR4 as a putative htt- interacting protein. Co-ip experiments provided evidence in support of this, and transactivation assays show significant inhibition of PPAR4 transactivation in htt-104Q expressing cells and in striatal-like neurons from the Q111/Q111 Hdh knock-in mouse model. At the same time, recent work has highlighted the potential importance of PPAR4 for mediating the pro-survival effects of retinoic acid, and a model has been proposed in which the ratio of two different retinoid binding proteins (FABP5 and CRABP-II) determines whether retinoic acid promotes cellular survival or cell death. We have begun to study this pathway in the striatum and in Hdh striatal-like cells, and have noted a marked decrease in FABP5 in HD. Furthermore, PPAR4 transactivation by its ligand GW501516 and by all-trans-retinoic acid (ATRA) is blunted in Q111/Q111 striatal-like neurons. Taken together, our studies suggest that PPAR4 is a target of polyQ-htt neurotoxicity, and offer a variety of tractable therapeutic targets, if our thesis is correct. In this project, we will determine the role of the retinoic acid - FABP5 - PPAR4 - PGC-11 pathway in normal neural health and in HD through the pursuit of three specific aims. First, we will test the hypothesis that altered retinoic acid - PPAR4 pathway function underlies HD pathogenesis by evaluating retinoid binding protein expression in HD, characterizing the htt - PPAR4 interaction, and testing if modulation of this pathway can rescue mitochondrial dysfunction in Hdh striatal-like neurons. Second, we will test the hypothesis that altered PPAR4-mediated retinoic acid signaling is sufficient to produce HD-like neurodegeneration by crossing floxed-STOP dominant-negative PPAR4 E411P transgenic mice (that we have already developed) with striatum- and cortex-specific drivers, cataloguing altered gene expression patterns in the striatum or cortex, and determining if altered expression and regulation of these PPAR4 target genes occur in HD. Third, we will test the hypothesis that PPAR4 transcription interference is a viable target for therapeutic intervention in HD by attempting a genetic rescue of HD with PPAR4-wt transgenic mice (that we have already developed), evaluating the effect of delivering PPAR4 agonists, and testing the therapeutic efficacy of delivery of FABP5.

Public Health Relevance

Studies of Huntington's disease (HD) and other related neurodegenerative disorders have highlighted the importance of mitochondrial function and bioenergetics in the maintenance of normal neural function. In this project, we will examine the exciting hypothesis that PPAR4 is involved in the maintenance of neuronal energy generation and that altered function of PPAR4 contributes to HD neurodegeneration. If PPAR4 is involved in this neurological disease, then tractable therapies to boost PPAR4 function would be tested, as highly selective and powerful pharmacological agonists for PPAR4 have been developed and are in use in humans, and PPAR4 mediates pro-survival signaling in response to retinoic acid.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065874-05
Application #
8616408
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (02))
Program Officer
Sutherland, Margaret L
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$625,986
Indirect Cost
$220,817
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Mason, Amanda G; Tome, Stephanie; Simard, Jodie P et al. (2014) Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum Mol Genet 23:1606-18
Sekiyama, Kazunari; Waragai, Masaaki; Akatsu, Hiroyasu et al. (2014) Disease-Modifying Effect of Adiponectin in Model of ?-Synucleinopathies. Ann Clin Transl Neurol 1:479-489
Haun, Florian; Nakamura, Tomohiro; Shiu, Alicia D et al. (2013) S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington's disease. Antioxid Redox Signal 19:1173-84
Tsunemi, Taiji; La Spada, Albert R (2012) PGC-1? at the intersection of bioenergetics regulation and neuron function: from Huntington's disease to Parkinson's disease and beyond. Prog Neurobiol 97:142-51
Kazemi-Esfarjani, Parsa; La Spada, Albert R (2010) Deja vu with a twist: transglutaminases in bioenergetics and transcriptional dysfunction in Huntington's disease. EMBO Mol Med 2:335-7