Targeting Bid to prevent programmed cell death in neurons.
Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-X(L), play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.
Culmsee
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C
Pharmaceutical Biology-Biotechnology, Department of Pharmacy, Ludwig-Maximilians-University, Butenandtstrasse 5-13, Building D, D-81377 Munich, Germany. carsten.culmsee@cup.uni-muenchen.de
Plesnila
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N
D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051336:Mitochondrial Membranes / Q000502:physiology; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology*; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019253:Proto-Oncogene Proteins c-bcl-2