Mechanisms of Cell Death in Neurodegenerative Diseases: Fashion, Fiction, and Facts

Abstract

Apoptosis has become a most popular concept of cell death. However, the term is now so widely used and employed in such general terms in relation to neurological diseases that its application is very problematic. In addition, with the exception of developmental conditions, there is essentially no evidence of apoptosis fulfilling the criteria of its classical definition in any of the important human neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Creutzfeldt‐Jakob disease. Importantly, a number of new cell death forms have been described in the literature and there is good reason to pay attention to these emerging concepts as they may provide a rationale for the development of disease‐specific therapies.

Activation of caspase 3, 9, 12, and Bax in masseter muscle of mdx mice during necrosis

“…Therefore, physiological cell death in organogenesis and pathological cell death had been considered to proceed by apoptosis and necrosis, respectively. This simple view is recently questioned since the involvement of apoptosis in neurodegenerative diseases was demonstrated, and apoptosis occurring during necrosis came to be discussed (Graeber et al 2002;Mattson 2000). However, there are few such studies, and the issue has not been clarified.…”

“…An apoptosis-like phenomenon that occurs during necrosis has been discussed in recent years (Graeber et al 2002;Mattson 2000). A related study indicated that, in addition to necrosis, an apoptosis-like phenomenon occurs in the muscle fibers of the mdx mouse model of muscular dystrophy.…”

Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death

“…Many distinct cell death phenotypes have been reported in animal models and human patient tissues of neurological diseases. 19,20 In fact it is somewhat rare to find dying cells with well-defined characteristics of apoptosis during the course of neurodegenerative diseases, including Parkinson disease and Alzheimer disease. 19 Moreover, cell death can be shifted between alternative pathways when one pathway is blocked.…”

“…19,20 In fact it is somewhat rare to find dying cells with well-defined characteristics of apoptosis during the course of neurodegenerative diseases, including Parkinson disease and Alzheimer disease. 19 Moreover, cell death can be shifted between alternative pathways when one pathway is blocked. 21 The daunting complexity of cell death mechanisms presents an immense challenge to find ways to intervene in dysregulated cell death conditions.…”

Linking Selective Vulnerability to Cell Death Mechanisms in Parkinson's Disease

“…13 In addition to selective vulnerability, the other major unsolved research question related to neurodegenerative disorders is the mechanism of neuronal death. Although apoptotic cell death is an appealing mechanism for neuronal loss in degenerative disease, 14 and cells with morphological features consistent with apoptosis are sometimes detected in Parkinson's disease, 15 there is increasing experimental evidence that apoptosis probably does not play a major role in neuronal loss in the substantia nigra in Parkinson's disease. 16,17 Postmortem artifacts, specifically postmortem DNA fragmentation, may account for at least some of the reports of apoptosis in the substantia nigra that relied on terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling techniques.…”