Huntington's disease (HD) is a relentlessly progressive autosomal dominant neurodegenerative disorder characterized by involuntary movements and cognitive decline. HD results from a CAG trinucleotide repeat expansion in the coding region of the huntingtin (htt) gene, and pathogenesis stems from production of htt protein with an expanded polyglutamine tract. We found that the mitochondrial dysfunction and metabolic deficits in HD result from transcriptional dysregulation of peroxisome proliferator-activated receptor [PPAR] gamma coactivator-1 alpha (PGC-????To determine the basis for PGC ???transcription interference in HD, we performed an unbiased screen for htt-interacting protins, and identified PPARs as candidate interactors. When we evaluated the different PPARs, we documented a physical interaction between PPAR? and htt in the cortex of BAC-HD97 transgenic mice, and confirmed that PPAR? is highly expressed in neurons. Mutant htt repressed PPAR? transactivation in neurons from BAC-HD97 mice, but could be rescued by PPAR? agonist treatment or over-expression. These findings formed the basis for our initial R01 project where we proposed to determine the role of the PPAR?-PGC-1? pathway in HD pathogenesis, define the function of PPAR? in the CNS, and test if PPAR? agonist therapy might be a viable treatment paradigm for HD and related disorders. In the last funding cycle, we confirmed the importance of the PPAR?-PGC-1? pathway in HD by documenting that htt physically interacts with PPAR? and represses PPAR? transactivation function to yield mitochondrial dysfunction and neurotoxicity, and determined that transgenic mice expressing dominant-negative PPAR? in the striatum recapitulate HD-like phenotypes. Furthermore, we observed neurological disease phenotypes in mice expressing dominant-negative PPAR?, thereby identifying neurons as a cell type where PPAR? function is essential for homeostasis. Finally, we validated a selective and potent PPAR? agonist, KD3010, as capable of rescuing htt neurotoxicity, and performed a preclinical trial of KD3010 in HD mice, where we documented significant improvements in motor function, neurodegeneration, and survival. In this renewal proposal, we will determine how PPAR? promotes neuroprotection by examining the effects of PPAR? on bioenergetics function, autophagy, and mitochondrial quality control. We will determine how PPAR? counters htt neurotoxicity by defining the cistrome and active regulome of PPAR? in normal neurons and HD neurons, and we will seek the basis for PPAR? neuroprotection by transcriptome analysis of HD mice treated with PPAR? agonist to identify genes and pathways required for PPAR? neuroprotection. To evaluate the contribution of such genes and pathways to PPAR? neuroprotection, we will test if expression modulation of target genes is sufficient to produce rescue in BAC-HD and HD patient neurons, or is capable of preventing rescue by PPAR? agonists.

Public Health Relevance

In the last funding cycle, we set out to determine the role of the PPAR?-PGC-1? pathway in HD, to define the function of PPAR? in the CNS, and to test if PPAR? agonist therapy might be a viable treatment for HD and related disorders; we found that huntingtin (htt) protein physically interacts with PPAR? and represses PPAR? transactivation function to yield mitochondrial dysfunction and neurotoxicity, and determined that transgenic mice expressing dominant-negative PPAR? in the striatum recapitulate HD-like phenotypes. We observed neurological disease phenotypes in mice expressing dominant-negative PPAR?, thereby identifying neurons as a cell type where PPAR? function is essential for homeostasis, validated a selective and potent PPAR? agonist, KD3010, as capable of rescuing htt neurotoxicity, and documented significant improvements in motor function, neurodegeneration, and survival in HD mice treated with KD3010 agonist. In this renewal proposal, we will determine how PPAR? promotes neuroprotection by examining the effects of PPAR? on bioenergetics function, autophagy, and mitochondrial quality control, by defining the cistrome and active regulome of PPAR? in normal neurons and HD neurons, by performing transcriptome analysis of HD mice treated with PPAR? agonist, and by validating identified PPAR? target genes and pathways in directed experiments in HD primary neurons cultured from BAC transgenic mice or derived from HD patient stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS065874-06
Application #
9113786
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
2010-02-01
Project End
2021-01-31
Budget Start
2016-02-15
Budget End
2017-01-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
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
Dickey, Audrey S; Sanchez, Dafne N; Arreola, Martin et al. (2017) PPAR? activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med 9:
Dickey, Audrey S; Pineda, Victor V; Tsunemi, Taiji et al. (2016) PPAR-? is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med 22:37-45
Eschbach, Judith; von Einem, Björn; Müller, Kathrin et al. (2015) Mutual exacerbation of peroxisome proliferator-activated receptor ? coactivator 1? deregulation and ?-synuclein oligomerization. Ann Neurol 77:15-32
Cortes, Constanza J; La Spada, Albert R (2015) Autophagy in polyglutamine disease: Imposing order on disorder or contributing to the chaos? Mol Cell Neurosci 66:53-61
Cortes, Constanza J; La Spada, Albert R (2014) The many faces of autophagy dysfunction in Huntington's disease: from mechanism to therapy. Drug Discov Today 19:963-71
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
Mason, Amanda G; Tomé, 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
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
Ward, Jacqueline M; La Spada, Albert R (2012) The expanding world of stem cell modeling of Huntington's disease: creating tools with a promising future. Genome Med 4:68
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

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