Inhibition of axotomy-induced neuronal apoptosis by extracellular deliveryof a Bcl-XL fusion protein

Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegene rative disease, and trauma. To test a new anti-apoptosis strategy for neuro protection, we engineered nontoxic components of anthrax toxin into a Bcl-X L delivery system. Delivery of Bcl-XL by this system prevented apoptosis of cultured rat cerebellar granule cells and macrophages, and the prevention depended on both the Bcl-XL and the anthrax toxin receptor binding/transloc ation moieties. Furthermore, neuronal death in vivo in a retinal ganglion c ell model of axotomy-induced apoptosis was inhibited by administration of t his fusion protein. Thus, Bcl-XL protein can he delivered into cells from t he medium or interstitial space, offering a new way to block apoptosis upst ream of many caspases and the mitochondria dysfunction phase of apoptosis.