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Does apoptosis have a role in neurodegeneration? Cells within the central nervous system die during both acute and chronic neurodegenerative disorders. Since the morphological and biochemical features of apoptosis were first described, neuroscientists have been asking whether this cell death is due to apoptosis and whether elucidating the mechanisms of apoptosis can provide new treatment strategies for intractable diseases such as stroke, Alzheimer's disease, and Huntington's disease. Detecting apoptosis Much debate has ensued. Firstly, cell death in the central nervous system may not fit perfectly with our current classification of apoptosis and necrosis, which was defined using peripheral cells. Some of the methods used may not distinguish conclusively between apoptosis and necrosis. For example, transferase-mediated dUTP nick end labelling (TUNEL), a staining method that detects the broken ends of DNA within cells, is used to provide evidence of apoptosis. However, DNA can be fragmented in necrosis too. Secondly, clinical symptoms may result from loss of neuronal function rather than apoptotic cell death. Many chronic neurodegenerative diseases are associated with intracellular aggregates of mutated proteins that cannot readily be disrupted, even by aggressive laboratory procedures. Such deposits may compromise neuronal function[---]for example, by blocking transport of nutrients along axons. A study of Huntington's disease in mice has shown that if generation of the mutant protein is halted, the aggregates are dissolved by the proteasome (the cellular machinery for removing unwanted proteins) and the neurological scores of the mice improve.[1] This suggests that, initially at least, symptoms may result from compromised neuronal function, with cell death having a subsequent role. Supporting evidence Evidence supporting a role for apoptosis in neurodegenerative diseases has come from studying rodent brain cells and by manipulation in animal models of the levels of expression or activity of key molecules involved in apoptosis. Active caspases, the proteases activated during apoptosis, have been detected in dying neurones taken from patients with Alzheimer's disease. These enzymes can cleave [beta ]-amyloid, a protein implicated in the pathogenesis of Alzheimer's, generating a pro-apoptotic protein.[2] Furthermore, [beta ]-amyloid can induce apoptosis in cultured neurones,[3] but cells lacking caspases become resistant to [beta ]-amyloid. Similarly, although normal huntingtin, which when mutated caused Huntington's disease, is required for survival of neurones, mutant huntingtin can induce apoptosis of neurones.[4] Huntingtin can also be cleaved by caspases, and cleavage is enhanced by mutation of the protein.[5] Preventing cleavage by caspases reduces the toxicity of the mutant huntingtin. Such studies provide circumstantial evidence that apoptosis participates in chronic neurodegeneration. Some of the best evidence for the role of apoptosis in neurodegeneration comes from studies of brain ischaemia or stroke (figure). Although necrosis predominates in the severely ischaemic core of injured tissue, apoptosis occurs in the less ischaemic region that surrounds the core.[6] Up regulation of several proteins that participate in apoptosis (for example, caspase-3) has been detected in stroke damaged brain tissue, and animals that have been engineered to overexpress anti-apoptotic proteins or that have been treated with caspase inhibitors show less damaged tissue after experimentally induced stroke. The evidence therefore suggests that apoptosis has a role in neurodegeneration, and the studies described above highlight the possibility that pro-apoptotic agents such as caspases might be new targets for therapeutic intervention. Caspase inhibitors would seem especially applicable to situations of acute degeneration such as stroke. It remains to be seen whether they can also be used for slowly progressing chronic neurodegenerative conditions, where neuronal function may fail before cell death removes the damaged neurone. Footnotes Funding: RG is supported by the Wellcome Trust. Competing interests: None declared. References 1. Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 2000; 101: 57-66[Medline]. 2. Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang JQ, et al. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-ß precursor protein and amyloidogenic Aß peptide formation. Cell 1999; 97: 395-406[Medline]. 3. Barinaga M. Is apoptosis key in Alzheimer's disease? Science 1998; 281: 1303-1304[Full Text]. 4. Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S. Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci 2001; 24: 182-188[Medline]. 5. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet 1996; 13: 442-449[Medline]. 6. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22: 391-397[Medline]. Rosemary M Gibson, research fellow. School of Biological Sciences, University of Manchester, Manchester M13 9PT BMJ 2001;322:1539-1540 ( 23 June ) http://bmj.com/cgi/content/full/322/7301/1539?lookupType=volpage&vol=322&fp= 1539&view=short janet paterson: an akinetic rigid subtype, albeit perky, parky . pd: 54/41/37 cd: 54/44/43 tel: 613 256 8340 email: [log in to unmask] . snail mail: 375 Country Street, Apt 301, Almonte, Ontario, Canada, K0A 1A0 . a new voice: the nnnewsletter: http://groups.yahoo.com/group/janet313/ . a new voice: the wwweb site: http://www.geocities.com/janet313/ . ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn