. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003 Apr 3;348(14):1365-75. PubMed.


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  1. How to die?
    Cell dysfunction and death is a central feature of many neurodegenerative diseases. What yet remains to be dissected is the exact nature and mechanism of cell death and the role of caspases in dysfunction and death in neurodegenerative diseases (Raina et al., 2001). The dogma of cell death in amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) has been synopsized in this well written review, "Apoptosis and Caspases in Neurodegenerative Diseases" by Robert Friedlander (2003). After reviewing the general aspects of caspase regulation, the review highlights two important diseases, namely amyotrophic lateral sclerosis (ALS) and Huntington's Disease (HD). The author presents evidence for greater duration of survival in transgenic ALS mice that also express a mutant caspase1 gene and hence are also presumably deficient in caspase 1 activity. The hypothetical temporal sequence of events shown in Figure 4 would have been made more dramatic if it included histopathological data of caspase 1 activation in the anterior horn cells of the spinal cord in the symptomatic and later stages.

    In HD, with the advent of transgenic models, the author points out the demonstration in these models of novel pathways of death that are neither apoptotic nor necrotic. Furthermore, the role of caspase 1 in HD seems to be relegated to proteolytic processing of the Huntingtin protein. Finally, the author highlights the current interest in the neuroprotective properties of minocycline, in the tetracycline class of antibiotics.

    It seems to be difficult to get a handle on what is really going on with caspases and chronic neurodegenerative diseases. In Alzheimer disease (AD), we have shown that although initiator caspases may get activated, it does not follow that the apoptotic signal is fully and faithfully transmitted downstream (Raina et al., 2001). Indeed, in such postmitotic neurons, the regulation of caspase physiology and pathophysiology may be altered to include novel functionality. More important, however, is the temporal dichotomy between the chronicity of neurodegenerative conditions such as AD and the acuteness of apoptotic and apoptotic-like events. The end-stage phenotype of the cell death program is know as apoptosis; it requires only 16-24 hours for completion and therefore, in a chronic disease like AD with an average clinical duration of almost 10 years, less than 1 in about 4,000 cells should be undergoing apoptosis at any given time (Perry et al., 1998). This means that the apoptotic events should be rare in AD to explain the absence of end-stage apoptotic morphology. However, the number of neurons demonstrating early apoptotic features and the amount of DNA fragmentation is extensive (Perry et al., 1998). Additionally, the stereotypical presentation that defines the terminal phases of cell death programs, such as chromatin condensation, apoptotic bodies, and blebbing, have never been observed in AD. Furthermore, since the putative apoptotic population is not synchronous, we should be able to detect a partial if not a complete spectrum of the ongoing apoptotic process at any given time, especially given the chronic nature of AD. We have no difficulty in detecting mitotic or even meiotic substages in tissues (McShea et al., 1997; Ogawa et al., 2003). For these reasons, the complete failure to detect apoptosis in AD, especially given its signature morphology, is quite puzzling.—Arun K. Raina, Xiongwei Zhu, George Perry and Mark A. Smith. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio USA; mas21@po.cwru.edu


    . Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003 Apr 3;348(14):1365-75. PubMed.

    . Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol. 1997 Jun;150(6):1933-9. PubMed.

    . Increased p27, an essential component of cell cycle control, in Alzheimer's disease. Aging Cell. 2003 Apr;2(2):105-10. PubMed.

    . A suicide note from Alzheimer disease neurons?. Nat Med. 1998 Aug;4(8):897-8. PubMed.

    . Abortive apoptosis in Alzheimer's disease. Acta Neuropathol. 2001 Apr;101(4):305-10. PubMed.

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