Accession Number : ADA492405


Title :   Signaling Pathways that Mediate Neurotoxin-Induced Death of Dopamine Neurons


Descriptive Note : Final rept. 1 Nov 2003-31 Oct 2008


Corporate Author : COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO


Personal Author(s) : Heidenreich, Kim A


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a492405.pdf


Report Date : 01 Nov 2008


Pagination or Media Count : 95


Abstract : Parkinson s disease (PD) is characterized by progressive loss of dopaminergic neurons in the nigrostriatal pathway resulting in significant motor dysfunction. The pathology of PD is mimicked by exposure to 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) or the pesticide rotenone. These neurotoxins inhibit complex I of the mitochondrial respiratory chain resulting in the production of reactive oxygen species (ROS) and increased cytosolic calcium. We hypothesize that ROS promotes opening of the mitochondrial permeability transition pore which triggers the death pathway. In parallel, increases in cytosolic calcium leads to oxidative stress and activation of c-Jun-NH2-terminal kinase (JNK). JNK/c-Jun signaling augments activation of the mitochondrial apoptotic cascade by suppressing Bcl-2 pro-survival signals via phosphorylation of Bcl-2 or transcription of the BH3-only, Bcl-2 antagonist Bim. The interactions between the oxidative stress pathway, the JNK/c-Jun signaling cascade, and the mitochondrial apoptotic machinery ultimately determine the fate of dopamine neurons. We will utilize primary ventral mesencephalic cultures obtained from E15 embryonic rats to investigate our hypothesis. The data obtained should lead to the identification of promising therapeutic strategies to slow or halt the dopaminergic neurodegeneration that occurs during progression of PD.


Descriptors :   *NEUROPHYSIOLOGY , *PARKINSONS DISEASE , *NEUROTOXINS , *DOPAMINE , NERVE CELLS , LOSSES , PATHOLOGY , CULTURES(BIOLOGY) , CENTRAL NERVOUS SYSTEM , DYSFUNCTION , MOTOR NEURONS , MITOCHONDRIA , DEGENERATION(PHYSIOLOGY) , RESPIRATORY SYSTEM , OXIDATION , IDENTIFICATION , BRAIN , IN VITRO ANALYSIS


Subject Categories : Psychology
      Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE