Bioenergetic Approaches and Inflammation of MPTP Toxicity
Abstract
This project was to develop novel therapies for Parkinsons Disease (PD), to test the effects of human dopaminergic stem cells, and to utilize metabolic profiling to develop biomarkers for PD. We developed a new transgenic mouse model of PD by expressing the LRRK2 mutation, R1441G, in the full-length human LRRK2 protein utilizing a bacterial artificial chromosome (BAC). These mice develop a profound parkinsonian phenotype in which they become markedly slowed with a flexed postured and impaired functioning using the rotarod. They have impaired release of dopamine as assessed using microdialysis and despite a normal complement of dopaminergic neurons, these mice showed axonal pathology in which there was phosphorylated tau, which formed spheroids. We carried out studies of PINK1 in cultured neurons and demonstrated that PINK 1 deficiency results in mitochondrial impairment. We also made a knockout PINK1 mouse. We utilized HPLC coupled to coularray electrochemical detection to perform metabolomic profiling. We showed that we could separate the patients with LRRK2 mutations from idiopathic PD and controls. Similarly, we could separate gene positive at risk from both controls and LRRK2 mutation negative subjects. Lastly, we found that administration of triterpenoids which activate the Nrf2/ARE pathway are neuroprotective against MPTP. These studies have continued over the last year and we have been able to make further progress in this area in meeting the research goals outlined in our tasks.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2010
- Accession Number
- ADA613916
Entities
People
- M. F. Beal
Organizations
- Cornell University