Protection of Neuronal Cells from Apoptosis by Hsp27 Delivered with a Herpes Simplex Virus-based Vector (1999)

Overexpression of the gene encoding the 70-kDa heat shock protein (hsp70) has previously been shown to protect neuronal cells against subsequent thermal or ischemic stress. It has no protective effect, however, against stimuli that induce apoptosis, although a mild heat shock (sufficient to induce hsp synthesis) does have a protective effect against apoptosis. We have prepared disabled herpes simplex virus-based vectors that are able to produce high level expression of individual hsps in infected neuronal cells without damaging effects. We have used these vectors to show that hsp27 and hsp56 (which have never previously been overexpressed in neuronal cells) as well as hsp70 can protect dorsal root ganglion neurons from thermal or ischemic stress. In contrast, only hsp27 can protect dorsal root ganglion neurons from apoptosis induced by nerve growth factor withdrawal, and hsp27 also protects the ND7 neuronal cell line from retinoic acid-induced apoptosis. However, hsp70 showed no protective effect against apoptosis in contrast to its anti-apoptotic effect in non-neuronal cell types. These results thus identify hsp27 as a novel neuroprotective factor and show that it can mediate this effect when delivered via a high efficiency viral vector. Overexpression of the gene encoding the 70-kDa heat shock protein (hsp70) has previously been shown to protect neuronal cells against subsequent thermal or ischemic stress. It has no protective effect, however, against stimuli that induce apoptosis, although a mild heat shock (sufficient to induce hsp synthesis) does have a protective effect against apoptosis. We have prepared disabled herpes simplex virus-based vectors that are able to produce high level expression of individual hsps in infected neuronal cells without damaging effects. We have used these vectors to show that hsp27 and hsp56 (which have never previously been overexpressed in neuronal cells) as well as hsp70 can protect dorsal root ganglion neurons from thermal or ischemic stress. In contrast, only hsp27 can protect dorsal root ganglion neurons from apoptosis induced by nerve growth factor withdrawal, and hsp27 also protects the ND7 neuronal cell line from retinoic acid-induced apoptosis. However, hsp70 showed no protective effect against apoptosis in contrast to its anti-apoptotic effect in non-neuronal cell types. These results thus identify hsp27 as a novel neuroprotective factor and show that it can mediate this effect when delivered via a high efficiency viral vector. The heat shock proteins (hsps) 1The abbreviations hsp(s)heat shock protein(s)HSVherpes simplex virusDRGdorsal root ganglionBHKbaby hamster kidneyNGFnerve growth factorm.o.i.multiplicity of infection were originally identified on the basis of their increased synthesis following exposure to elevated temperature. Subsequently, however, they were shown to be induced by a wide variety of other stresses in many different cell types (for review see Refs. 1Lindquist S. Annu. Rev. Biochem. 1986; 55: 1151-1191Crossref PubMed Google Scholar, 2Lindquist S. Craig E.A. Annu. Rev. Genet. 1988; 22: 631-677Crossref PubMed Scopus (4419) Google Scholar, 3Latchman D.S. J. R. Coll. Physicians Surg. 1991; 25: 295-300PubMed Google Scholar) including neuronal cells exposed to ischemia (4Nowak T.S.J. J. Neurochem. 1985; 45: 1635-1641Crossref PubMed Scopus (230) Google Scholar), amphetamine treatment (5Miller E. Raese J.B. Morrison-Bogorad M. J. Neurochem. 1991; 56: 2060-2071Crossref PubMed Scopus (120) Google Scholar), or to sodium arsenite (6Lowenstein D.H. Chan P.H. Miles M.F. Neuron. 1991; 7: 1053-1060Abstract Full Text PDF PubMed Scopus (256) Google Scholar). Such induction of the hsps has been shown to have a protective effect against exposure to a subsequent stress in a variety of cell types. Thus, for example, exposure of primary neuronal cultures to a mild heat stress or ischemic stress sufficient to induce the hsps has been shown to be protective against subsequent exposure to the excitotoxin glutamate or to severe heat or ischemic stress (6Lowenstein D.H. Chan P.H. Miles M.F. Neuron. 1991; 7: 1053-1060Abstract Full Text PDF PubMed Scopus (256) Google Scholar, 7Rordorf G. Koroshetz W.J. Bonventre J.V. Neuron. 1991; 7: 1043-1052Abstract Full Text PDF PubMed Scopus (192) Google Scholar, 8Amin V. Cumming D.V.E. Coffin R.S. Latchman D.S. Neurosci. Lett. 1995; 200: 85-88Crossref PubMed Scopus (39) Google Scholar), whereas similar exposure in vivo can protect against damaging effects caused by subsequent exposure to light (9Barbe M.F. Tytell M. Gower D.J. Welch W.J. Science. 1988; 241: 1817-1820Crossref PubMed Scopus (388) Google Scholar) or ischemia (10Chopp M. Chen H. Ho K.-L. Dereski M.O. Brown E. Hetzel F.W. Welch K.M. Neurology. 1989; 39: 1396-1398Crossref PubMed Google Scholar, 11Kitagawa K. Matsumoto M. Tagaya M. Hata R. Keda H. Ninobe M. Handa N. Fukunaga R. Kimura K. Mikshiba K. Kamada T. Mol. Brain Res. 1990; 528: 21-24Crossref Scopus (1056) Google Scholar). heat shock protein(s) herpes simplex virus dorsal root ganglion baby hamster kidney nerve growth factor multiplicity of infection In a number of cases the protective effect of a mild hsp-inducing stress can be reproduced by the artificial overexpression of a single hsp. Thus, for example, dorsal root ganglion (DRG) neurons can be protected against thermal or ischemic stress by overexpression of either the 70-kDa hsp (hsp70) or the 90-kDa hsp (hsp90) (12Uney J.B. Kew C.N.N. Staley K. Tyers P. Sofroniew M.V. FEBS Lett. 1993; 334: 313-317Crossref PubMed Scopus (59) Google Scholar, 13Amin V. Cumming D.V.E. Latchman D.S. Neurosci. Lett. 1996; 206: 45-48Crossref PubMed Scopus (92) Google Scholar, 14Wyatt S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar), and a similar protective effect of hsp70 and hsp90 has also been observed in the ND7 immortalized cell line derived from sensory neurons (15Mailhos C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar). Interestingly, Fink et al. (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) were able to protect cultured hippocampal neurons against subsequent heat shock using a herpes simplex virus (HSV)-derived amplicon vector expressing hsp70 indicating that this effect applies to neurons derived from both the central and peripheral nervous systems. Moreover, the use of an HSV-based vector opens up the possibility of testing the protective effect of the hsps in vivo and of their ultimate therapeutic use in man. Such vectors can effectively deliver genes to neuronal cells following in vivo injection and may be useful for gene therapy procedures (for review see Refs. 17Coffin R.S. Latchman D.S. Latchman D.S. Genetic Manipulation of the Nervous System. Academic Press, Lndon1995: 99-114Crossref Google Scholar and 18Fink D.J. DeLuca N.A. Goins W.F. Glorioso J.C. Annu. Rev. Neurosci. 1996; 19: 265-287Crossref PubMed Scopus (148) Google Scholar). Such a possibility is of particular interest in view of the finding that a prior mild heat shock can protect neonatal DRG neurons against apoptosis induced by withdrawal of nerve growth factor (15Mailhos C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar) and similarly protects ND7 cells against apoptosis induced by serum withdrawal and addition of retinoic acid (19Mailhos C. Howard M.K. Latchman D.S. Neuroscience. 1993; 55: 621-627Crossref PubMed Scopus (154) Google Scholar). Thus the ability to manipulate the rate of apoptosis would be of use in neurological diseases such as muscular dysgenesis (20Oppenheim R.W. Annu. Rev. Neurosci. 1991; 14: 453-501Crossref PubMed Scopus (2759) Google Scholar) or spinal muscular atrophy (21Gamstrop I. Sarnet H.B. Progressive Spinal Muscular Atrophies. Raven Press, Ltd., New York1984Google Scholar) which involve changes in the normal level of neuronal cell apoptosis during development as well as in later onset diseases such as Alzheimer's or Parkinson's diseases where the excessive neuronal cell death may be apoptotic in nature (20Oppenheim R.W. Annu. Rev. Neurosci. 1991; 14: 453-501Crossref PubMed Scopus (2759) Google Scholar). however, it has thus to identify a single hsp overexpression in neuronal cells can protect from apoptosis. Thus, overexpression of hsp70 can protect different non-neuronal cell types from apoptosis including cells Res. 1996; PubMed Scopus Google Scholar), normal Chen Res. 1996; PubMed Scopus Google Scholar), and cell cell C. Mol. 1997; PubMed Scopus Google Scholar, K. 1995; PubMed Scopus Google Scholar). In contrast, however, overexpression of hsp70 or hsp90 in ND7 cells (15Mailhos C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar) or DRG neurons S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar) does the protective effect of mild heat shock against subsequent apoptotic in the of Fink et al. (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) overexpression of hsp70 an vector protect hippocampal neurons against glutamate which may by apoptosis S. T. T. K. K. Biochem. Res. 1991; PubMed Scopus (230) Google Scholar). It is that the protective effect of heat shock against apoptosis in neuronal cells be reproduced by hsp70 its protective effect in other cell types. The protective effect involve hsp such as hsp27 which has also been shown to protect non-neuronal cell types against apoptosis Res. 1996; PubMed Scopus Google Scholar, P. K. 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ND7 cells were in serum and infected as exposure to either heat shock or ischemia prior to of cell by induce the cells to and or apoptosis, they were to of a of and and sodium retinoic acid to a of to the of cells apoptosis. has previously been shown to induce cell death by apoptosis in these cells M.K. Mailhos C. Latchman D.S. J. Neurochem. 1993; PubMed Scopus Google Scholar). ND7 cells were and infected an of of the vectors expressing or of the serum of retinoic the cultures were for were and the cells were for were in and to the The were using and the of apoptotic cells were in of view for to and to ND7 cells or primary DRG cells in The were in and in a heat for cells) or primary DRG (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) by to a for for a of cells) or as in (15Mailhos C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google C. Howard M.K. Latchman D.S. Neuroscience. 1993; 55: 621-627Crossref PubMed Scopus (154) Google Scholar). The ND7 cells were and in of for cell DRG neurons were and similar to previously S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar). can be in by the cells in a of high and and of and K. M. J. 1991; Google Scholar). ND7 and DRG cells were cultured in a and or infected the prior to The cells were for in either or ischemic K. M. J. 1991; Google Scholar). ND7 cells were as and primary DRG neurons were and and in The of cell death by the of cells able to by an of in to cells that been by or by addition to the cell were for and the of cells able to were on to as previously (19Mailhos C. Howard M.K. Latchman D.S. Neuroscience. 1993; 55: 621-627Crossref PubMed Scopus (154) Google Scholar, S. P. Latchman D.S. 1993; PubMed Scopus Google Scholar), and either an see R.M. 1985; PubMed Scopus Google Scholar), or to the other hsps from were infection as and in the of hsp induction in to cells infected the of protein by of in protein from cells an HSV-based amplicon vector hsp70 has been (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar). a an of and is by cells and a virus (for review of vectors see Refs. 17Coffin R.S. Latchman D.S. Latchman D.S. Genetic Manipulation of the Nervous System. Academic Press, Lndon1995: 99-114Crossref Google Scholar and 18Fink D.J. DeLuca N.A. Goins W.F. Glorioso J.C. Annu. Rev. Neurosci. 1996; 19: 265-287Crossref PubMed Scopus (148) Google Scholar). of a of virus and amplicon vector. from the that it a viral of amplicon and virus different although a efficiency amplicon growth has been C. S. P. P. J. 1996; PubMed Google Scholar). 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PubMed Scopus Google Scholar) which are cells to and growth of the overexpression of and hsp27 the virus to observed in cells In contrast, the hsp90 virus show overexpression of hsp90 results were also in cells and in ND7 cells which are of neuronal that hsps were also overexpressed without virus and in particular in cells of neuronal expression in infected ND7 to hsp27 hsp56 or hsp70 using from cells cells infected virus expressing or virus expressing the hsp as in the hsp90 virus expression of hsp90 it used for these However, the other were used to ND7 cells and primary DRG ND7 cells a cell of neuronal to the protective effect of the against In these cells infected the virus expressing showed either or stress to that observed in ND7 cells that the virus have effect in these Moreover, the virus able to protect ND7 cells from subsequent exposure to both a severe thermal or ischemic results ND7 cells a hsp70 (15Mailhos C. Howard M.K. Latchman D.S. J. 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In these cells infected expressing or hsp56 showed of to whereas cells infected the hsp70 virus showed a protective effect, only the In contrast, cells infected the virus showed a both and the onset of treatment both the virus a protective effect that to this virus and observed the other that to a effect of viral such as an in the rate of cell that the protective effect of the virus to apoptosis, for which is of apoptosis, by serum and addition of retinoic In these the cultures infected the virus showed a in the number of cells whereas this observed in the cells infected the other These results that overexpression of hsp27 can protect ND7 cells from apoptosis as well as against whereas protective effect of hsp70 against cell death does to involve in the number of cells apoptosis as by the the of these results to the in vivo similar of cultured neonatal dorsal root ganglion In these the and protected DRG neurons from both thermal and ischemic stress both Interestingly, in contrast to the in ND7 against both stresses also observed the although the effect that observed hsp70 or cells infected the virus showed similar to cells following exposure to either DRG following ischemia when infected vectors expressing DRG neuronal cultures were the an of to of The of against neurons prior to the and and in the ischemic The the of the of for the of the in in ND7 cells or in using of In to the effect of these on following an apoptotic their effect on the of DRG neurons following withdrawal of nerve growth factor which is a well of apoptosis J. 1988; PubMed Scopus Google Scholar). in the expressing hsp70 and hsp56 no protective effect in this whereas the virus expressing hsp27 a protective that the virus against apoptotic in the primary DRG neurons infected of the and exposed to in the virus a protective effect in this whereas no protective effect observed the the the of cell a number of in different types of non-neuronal cells have the protective effect of individual hsps for example, Refs. I. J. Biochem. 1991; PubMed Scopus Google Scholar, Latchman D.S. Res. 1991; PubMed Scopus Google Scholar, Latchman D.S. J. Mol. 1994; Full Text PDF PubMed Scopus Google Scholar, Latchman D.S. J. Mol. 1995; Full Text PDF PubMed Scopus Google Scholar), such have been and in primary neuronal Thus whereas overexpression of hsp70 has been shown to protect different types of cultured neuronal cells from subsequent thermal (12Uney J.B. Kew C.N.N. Staley K. Tyers P. Sofroniew M.V. FEBS Lett. 1993; 334: 313-317Crossref PubMed Scopus (59) Google V. Cumming D.V.E. Latchman D.S. Neurosci. Lett. 1996; 206: 45-48Crossref PubMed Scopus (92) Google Scholar, S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) or ischemic V. Cumming D.V.E. Latchman D.S. Neurosci. Lett. 1996; 206: 45-48Crossref PubMed Scopus (92) Google Scholar) it to protect from subsequent exposure to glutamate (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) or apoptosis induced by withdrawal of nerve growth factor S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar), a mild heat shock sufficient to induce the hsps does protect against these stimuli (6Lowenstein D.H. Chan P.H. Miles M.F. Neuron. 1991; 7: 1053-1060Abstract Full Text PDF PubMed Scopus (256) Google Scholar, 7Rordorf G. Koroshetz W.J. Bonventre J.V. Neuron. 1991; 7: 1043-1052Abstract Full Text PDF PubMed Scopus (192) Google C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar). overexpression of hsp90 has been shown to protect cultured sensory neurons from thermal and ischemic stress against withdrawal V. Cumming D.V.E. Latchman D.S. Neurosci. Lett. 1996; 206: 45-48Crossref PubMed Scopus (92) Google Scholar, 14Wyatt S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar), whereas the other hsps have been for their effects in neuronal These in the of genes to neuronal cells high efficiency by as well as the to cell expressing the gene of interest as can be for cell Moreover, cell of neuronal such as the ND7 cell line P. P. Latchman D.S. C. G. M. R. 1990; 241: PubMed Scopus Google Scholar), are used it is to cell as to of a expressing an individual hsp. have used a herpes simplex virus vector to deliver individual hsp genes high efficiency of cells are the virus shown and see Refs. M.K. T. P. Brown Coffin R.S. Latchman D.S. PubMed Scopus Google Scholar and M.K. Coffin R.S. Brown G. Latchman D.S. J. Mol. Neurosci. 1997; PubMed Google Scholar) to primary neurons and ND7 cells of to be in cells expressing the hsp. Moreover, the and M.K. T. P. Brown Coffin R.S. Latchman D.S. PubMed Scopus Google Scholar, M.K. Coffin R.S. Brown G. Latchman D.S. J. Mol. Neurosci. 1997; PubMed Google Scholar) that the disabled virus vector use does produce effects or effects on cell which would its use in the protective effects of HSV-based vector previously used to hsp70 in hippocampal although the other hsps were (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar). Moreover, the vector used by Fink et al. (16Fink S.L. Chang L.K. Ho D.Y. Sapolsky R.M. J. Neurochem. 1997; 68: 961-969Crossref PubMed Scopus (116) Google Scholar) is an amplicon in which the gene to be overexpressed is a vector an of and of this amplicon an viral thus a virus to the proteins in review of vectors see Refs. 17Coffin R.S. Latchman D.S. Latchman D.S. Genetic Manipulation of the Nervous System. Academic Press, Lndon1995: 99-114Crossref Google Scholar and 18Fink D.J. DeLuca N.A. Goins W.F. Glorioso J.C. Annu. Rev. Neurosci. 1996; 19: 265-287Crossref PubMed Scopus (148) Google Scholar). the viral for use in is a of types of amplicon and different it to In contrast, have encoding individual hsps by a vector a viral gene encoding and to J. 1985; 55: PubMed Google Scholar). We have used these vectors to V. Cumming D.V.E. Latchman D.S. Neurosci. Lett. 1996; 206: 45-48Crossref PubMed Scopus (92) Google Scholar, C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar), and show that hsp70 can protect both ND7 cells and DRG neurons from both thermal and ischemic stress. protective effects can be these vectors in the as in Moreover, have these to other hsps effect has previously been in neuronal Thus, have shown that overexpression of hsp27 has a similar protective effect against thermal and ischemic stress in both ND7 cells and DRG whereas hsp56 has protective effect against both these stresses in DRG neurons in ND7 is of particular interest have previously shown that and hsp56 are overexpressed during ischemia in vivo Coffin R.S. M. Latchman D.S. Mol. Brain Res. 1996; PubMed Scopus Google Scholar). have shown that hsp27 can protect both ND7 cells and DRG neurons against stimuli which would induce apoptosis as well as against stimuli which induce In contrast, hsp56 no protective effect, and hsp70 only a effect against an apoptotic only in ND7 cells when cell were and no effect on the number of that hsp70 has only a protective effect in this which may be to be by the or that it is against apoptotic These results are in hsp70 using S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar, C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar) and other cells types Res. 1996; PubMed Scopus Google Scholar, Chen Res. 1996; PubMed Scopus Google Scholar, C. Mol. 1997; PubMed Scopus Google Scholar), neuronal cells be protected against apoptosis by overexpression of In contrast, results show the protective effect of hsp27 against cell death as well as against in neuronal effect to the virus and observed expressing or indicating that the be to effect of virus is the such a protective effect of hsp27 has been shown in neuronal although it has previously been observed in Res. 1996; PubMed Scopus Google Scholar, P. K. J. 1996; PubMed Scopus Google Scholar). In these the overexpression of hsp27 protected cells against apoptosis induced by the as well as by a protein P. K. J. 1996; PubMed Scopus Google Scholar). results this to a different cell and to of cell death retinoic acid treatment and factor These a protective for hsp27 against apoptotic stimuli in different cell as well as against stimuli such as elevated or although the of these effects has been shown to as an and overexpression to a to the of the T. K. J. M. J. 1991; PubMed Scopus Google Scholar, T. M. J. Biochem. 1988; Scholar). heat shock hsp27 is which may a either the and or the hsp27 to to other their and the of to and It is however, these changes produce a protective effect against apoptotic or the for its protective effect, it is that in which prior heat shock a protective effect against subsequent exposure to apoptotic stimuli S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar, C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar) can be in by the expression of hsp27 a of hsps induced by heat shock or other protective effect hsp the well protective effect of a prior heat shock against subsequent severe thermal or ischemic stress is to involve the elevated synthesis of hsp27 as well as of hsp27 as a protective protein a effect in of cell and nature of the stress hsp70 or other hsps such as hsp90 S. Mailhos C. Latchman D.S. Mol. Brain Res. 1996; 39: 52-56Crossref PubMed Scopus (39) Google Scholar, C. Howard M.K. Latchman D.S. J. Neurochem. 1994; 63: 1787-1795Crossref PubMed Scopus (115) Google Scholar) or hsp56 The induction of this protein in ischemia in vivo Coffin R.S. M. Latchman D.S. Mol. Brain Res. 1996; PubMed Scopus Google Scholar) that its artificial overexpression in vivo may a similar protective effect and may be of therapeutic in diseases such as its protective effect against apoptotic as well as neuronal cell death that it may be of use in gene therapy procedures neurological diseases such as Alzheimer's and Parkinson's The of an vector of gene in vivo R.S. Latchman D.S. Brown 1995; Scholar, M.K. T. P. Brown Coffin R.S. Latchman D.S. PubMed Scopus Google Scholar) expressing hsp27 testing of its therapeutic in apoptotic and cell death in the We for of primary DRG and for the of hsp and for the