Huntington's Disease (HD) is a debilitating genetic disorder involving progressive deterioration of psychiatric and motor function over a period of years, leading to death. Studies indicate that the expression of the transcriptional co-activator peroxisome proliferator activated receptor co-activator 1 (PGC-1) is decreased in striatum and muscle tissue from patients with HD and that mutant huntingtin (mHtt) interferes with normal expression and activity of PGC-1. Furthermore, polymorphisms in the PGC-1 gene influence the age of onset of motor symptoms. In light of the proposed role for PGC-1 in metabolic regulation, scientists have hypothesized that deficiencies in PGC-1 contribute to neuronal vulnerability and mitochondrial defects in HD. The roles of PGC-1 in the brain are not well-defined. PGC-1 is concentrated specifically in neurons that express the enzyme glutamic acid decarboxylase 67 (GAD67), and new data from the Cowell lab indicate that PGC-1 is required for the appropriate expression of the calcium buffer parvalbumin. Furthermore, PGC-1 null animals show abnormalities in GABAergic signaling, long-term potentiation, and motor function. Preliminary studies show that PGC-1 is consistently downregulated in cell culture models of HD, and the expression of PGC-1 and its targets parvalbumin and glucose transporter 4 are decreased in the striatum, hippocampus, and cortex in a mouse model. These data are interesting, considering that parvalbumin-positive (PV+) interneuron function is compromised in the cortex prior to the onset of motor symptoms in mouse models of HD. In addition, because of the strong feed-forward inhibitory effect PV+ neurons exert on medium spiny neurons and cortical pyramidal neurons, even slight disturbances in PV+ neuron function could profoundly influence striatal/cortical output and motor function. We propose that a deficiency in PGC-1 predisposes PV+ neurons to vulnerability in HD and compromises their ability to properly inhibit local projection neurons and coordinate motor output. The experiments proposed in this application will test this hypothesis by determining 1) the requirement for PGC-1 in striatal PV+ interneuron survival, morphology, signaling, calcium homeostasis, and motor function, 2) the effects of PGC-1 ablation on other vulnerable neuronal populations in the striatum, 3) the regional and cellular specificity of changes in PGC-1 and PGC-1-target gene expression in mouse models of HD, and 4) the impact of PGC-1 overexpression on cellular survival and motor function in a mouse model of HD. The proposed experiments are necessary to determine the cell autonomous and non-cell autonomous effects of PGC-1 dysfunction on neuronal viability and function with the goal of determining whether PGC-1 is an appropriate target for the treatment of HD.

Public Health Relevance

Huntington Disease (HD) is a devastating neurological disorder that occurs in as many as 7 in every 100,000 people. While the genetic basis for HD is known, there are no effective therapies available. These studies will test whether transcriptional pathways that control mitochondrial function and calcium homeostasis in interneurons have potential as targets for treatment of patients with HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070009-03
Application #
8247783
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$314,059
Indirect Cost
$99,684
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Dougherty, S E; Bartley, A F; Lucas, E K et al. (2014) Mice lacking the transcriptional coactivator PGC-1? exhibit alterations in inhibitory synaptic transmission in the motor cortex. Neuroscience 271:137-48
Dougherty, S E; Hollimon, J J; McMeekin, L J et al. (2014) Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells. Neurobiol Dis 62:160-71
Lucas, Elizabeth K; Dougherty, Sarah E; McMeekin, Laura J et al. (2014) PGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. J Neurosci 34:14375-87
Dougherty, S E; Reeves, J L; Lesort, M et al. (2013) Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington disease. Exp Neurol 240:96-102