Bcl-xL protects adult septal cholinergic neurons from axotomized cell death

Blömer, Ulrike; Kafri, Tal; Randolph‐Moore, Lynne; Verma, Inder M.; Gage, Fred H.

doi:10.1073/pnas.95.5.2603

Cited by 85 publications

(39 citation statements)

References 45 publications

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“…For example, nerve growth factor maintains the survival of sympathetic neurons only during neonatal maturation. Because Bcl-XL is widely expressed in the central nervous system during development (20) and its overexpression protects against a broad range of neurotoxic insults (32,33,56), LFn-⌬Bcl-XL may have broad potential to prevent apoptosis of different types of neurons resulting from different insults at different stages of development. Here we show LFn-⌬Bcl-XL protects cerebellar granule cells, a macrophage-related cell line, and retinal ganglion cells from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Liu¹,

Collier²,

Youle³

2001

Journal of Biological Chemistry

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Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegenerative disease, and trauma. To test a new anti-apoptosis strategy for neuroprotection, we engineered nontoxic components of anthrax toxin into a Bcl-XL 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/translocation moieties. Furthermore, neuronal death in vivo in a retinal ganglion cell model of axotomy-induced apoptosis was inhibited by administration of this fusion protein. Thus, Bcl-XL protein can be delivered into cells from the medium or interstitial space, offering a new way to block apoptosis upstream of many caspases and the mitochondria dysfunction phase of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Liu¹,

Collier²,

Youle³

2001

Journal of Biological Chemistry

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“…After HIV-1 vectors were described, replication-defective systems were engineered from molecular clones of non-primate and other primate lentiviruses [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In addition to their use in pre-clinical gene therapy research, lentiviral vectors have been important tools for basic science [20][21][22][23][24][25][26][27][28]. This review concentrates on virological fundamentals of FIV-based lentiviral vector development, and discusses some recent lentivirological controversies and vector applications.…”

Section: Introductionmentioning

confidence: 99%

FIV: from lentivirus to lentivector

Saenz

Poeschla

2004

J. Gene Med.

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SummaryMolecular virological understanding of the feline immunodeficiency virus (FIV) life cycle is increasing, facilitating rational derivation of improved vectors from this non-primate lentivirus. The packaging signal has been mapped, a central DNA flap has been identified, and class I integrase mutants have been validated. Vector systems with improved effectiveness and safety profiles are being applied by a number of laboratories in several pre-clinical models, with demonstrated efficacy in human tissues. The comparative lentivirological research that facilitates FIV vector development may also yield insights into the still enigmatic molecular basis for a signature lentiviral property with pathogenetic and therapeutic importance: permanent transgene integration in non-dividing cells. This review discusses virological aspects of lentiviral vector development, as well as some recent controversies and applications.

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“…B CL-xL is a potent inhibitor of programmed cell death and is abundantly expressed in neurons of the adult brain (1)(2)(3)(4)(5). BCL-xL localizes to the outer mitochondrial membrane (6) and has been suggested to protect cells from death by regulating export of ATP from mitochondria and͞or by blocking the activation of proapoptotic BCL-2-related proteins (7)(8)(9).…”

mentioning

confidence: 99%

Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals

Jonas

Hickman

Chachar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal death is often preceded by functional alterations at nerve terminals. Anti-and proapoptotic BCL-2 family proteins not only regulate the neuronal death pathway but also affect excitability of healthy neurons. We found that exposure of squid stellate ganglia to hypoxia, a death stimulus for neurons, causes a cysteine protease-dependent loss of full-length antiapoptotic BCL-xL, similar to previous findings in mammalian cells. Therefore, to determine the direct effect of the naturally occurring proapoptotic cleavage product of BCL-xL on mitochondria, recombinant N-truncated BCL-xL was applied to mitochondria inside the squid presynaptic terminal and to purified mitochondria isolated from yeast. Ntruncated BCL-xL rapidly induced large multi-conductance channels with a maximal conductance significantly larger than those produced by full-length BCL-xL. This activity required the hydrophobic C terminus and the BH3 domain of BCL-xL. Moreover, N-truncated BCL-xL failed to produce any channel activity when applied to plasma membranes, suggesting that a component of the mitochondrial membrane is necessary for its actions. Consistent with this idea, the large channels induced by N-truncated BCL-xL are inhibited by NADH and require the presence of VDAC, a voltagedependent anion channel present in the outer mitochondrial membrane. These observations suggest that the mitochondrial channels specific to full-length and N-truncated BCL-xL contribute to their opposite effects on synaptic transmission, and are consistent with their opposite effects on the cell death pathway.

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Bcl-xL protects adult septal cholinergic neurons from axotomized cell death

Cited by 85 publications

References 45 publications

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

FIV: from lentivirus to lentivector

Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals

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