[Abstract Title]. - Society for Neuroscience

Poster
253. Parkinson's Disease Models: Neuroprotective Mechanisms I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 253.10/X11
Topic: C.11.j. Neuroprotective mechanisms: Parkinson‟s disease models
Support: NRSA F32 DK075253
NPF mega projects in Parkinson Research
Title: PGC-1 alpha and Parkinson‟s disease: a putative transgenic model of neuroprotection
during oxidative stress
Authors: *J. M. SILVAGGI 1 , C. CHUNG 2 , A. SHEETS 1 , J. CLARK 3 , D. K. SIMON 3 , O.
ISACSON 2 , B. M. SPIEGELMAN 1 ;
1 Dana-Farber Cancer Inst., Boston, MA; 2 Harvard Med. Sch., Boston, MA; 3 Beth Israel
Deaconess Med. Ctr., Boston, MA
Abstract: Many studies suggest that the neurodegeneration observed in Parkinson‟s disease is
associated with mitochondrial dysfunction and damage through excess oxidative stress.
Unfortunately, current pharmacological approaches for the treatment of Parkinson‟s disease
patients do not alter the progression of the disease, but only aid in symptoms of the
neurodegeneration. New therapeutic approaches using gene therapy and delivery methods are
currently being investigated in pre-clinical trials, providing future avenues for the delay of
progression of the disease. An intriguing target of interest is the transcriptional coactivator PGC-
1 alpha, which is a master regulator of several pathways related to mitochondria and energy
homeostasis in a wide variety of tissues. PGC-1 alpha has also been shown to induce several
genes involved in the detoxification response for reactive oxygen species (ROS), and is itself
induced by increases in ROS. PGC-1 alpha null mice display defects in several regions of the
brain including severe lesions in the striatum and increased sensitivity to chemicals which model
the effects of Parkinson‟s disease and seizure. We are investigating the neuroprotective effects of
PGC-1 alpha in the substantia nigra (SN), the neuronal region affected in Parkinson‟s disease.
Neuroprotection will be assayed using oxidative stressors (MPTP) in a transgenic mouse model
in which PGC-1 alpha is overexpressed in the SN. Ultimately, microarray analysis will be
performed on laser captured SN cells to compare transgenic lines versus wild type mice, to
determine the global effect of PGC-1 alpha expression in dopaminergic neurons in vivo. In
parallel to in vivo studies, we are also investigating the transcription factor through which PGC-1
alpha coactivates the ROS detoxifying enzyme manganese superoxide dismutase (SOD2). Using
luciferase fusion constructs, we have found that PGC-1 alpha significantly coactivates the PPAR
(peroxisome proliferator activated receptor) transcription factors on the mouse SOD2 promoter.
Promoter analysis revealed putative peroxisome proliferator response elements (PPREs) in the
SOD2 promoter which when mutated blunt this coactivation effect. Electrophoretic mobility shift