Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription.
Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
Tatton
W G
WG
Department of Physiology/Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Chalmers-Redman
R M
RM
Ju
W Y
WY
Wadia
J
J
Tatton
N A
NA
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008959:Models, Neurological; D009336:Necrosis; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013482:Superoxide Dismutase