. The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3585-90. PubMed.


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  1. Data implicating aberrant activation of the cell cycle as a potential mechanism of cell death in neurodegenerative diseases have been presented in Alzforum a number of times previously (see Live Discussions 2002, and 2006), and are reviewed extensively in a recent compendium (Biochimica et Biophysica Acta Molecular Basis of Disease Volume 1772, Issue 4 pp. 391-508). The focus has hitherto been on Alzheimer disease and tauopathies for which there is extensive evidence of aberrant neuronal cell-cycle activation in postmortem tissue (1,2) and for which murine and Drosophila models have directly implicated cell-cycle mechanisms (3,4). Höglinger et al. now provide a thorough and well-designed set of experiments to implicate cell-cycle mechanisms in sporadic Parkinson disease (PD). Previously, tantalizing connections have been made among a number of genes implicated in familial PD and cell-cycle control, including parkin (reviewed in [5]). Parkin is a ubiquitin ligase, loss of function of which causes autosomal recessive Parkinson disease. Recently, it has been shown that parkin targets cyclin E, a regulator of the G1/S cell-cycle transition, to the proteasome for degradation. Furthermore, parkin overexpression attenuates the accumulation of cyclin E and rescues cultured neurons from kainate-induced cytotoxicity (6). In the present work, Höglinger et al. now show that

    • in sporadic PD a number of cell-cycle proteins are upregulated in susceptible dopaminergic neurons of the substantia nigra (SNc), including E2F-1 and PCNA, with some DA neurons in fact having replicated their DNA, as indicated by fluorescent in situ hybridization (FISH) probing for specific chromosomal loci;
    • multiple cell-cycle markers, including cyclins D, E, A, and B, are upregulated in cultured postmitotic DA neurons exposed to the neurotoxin MPP+. Further, these cells incorporate the thymidine analogue BrdU, indicating DNA synthesis, and the majority of BrdU+ cells double-label with an antibody to caspase-3;
    • in mice treated with MPTP, SNc DA neurons can be found which incorporate BrdU, indicating DNA synthesis, and which abnormally express E2F-1, phosphorylated retinoblastoma protein, and PCNA;
    • adult neurogenesis is not a likely explanation of cell-cycle marker re-expression because striatal injection of the retrograde tracer fluorogold shows neurons which incorporate PCNA are not newly synthesized;
    • in cultured DA neurons exposed to MPP+, inhibition of E2F-1 antisense oligonucleotides substantially inhibits apoptosis (measured by caspase-3 immunostaining), whereas caspase inhibition does not prevent BrdU incorporation, indicating that cell-cycle re-activation is upstream of apoptosis;
    • mice null for E2F-1 are modestly protected against MPP+-induced SNc DA neuron loss.

    This work is particularly commendable for its attention to detail. The demonstration of cell cycle-like mechanisms operating in PD brain tissue and in DA neurons exposed to MPP+ in vitro and in vivo using multiple assays, including antibodies to multiple cell-cycle regulators, FISH and BrdU, is very convincing. Further, the attempt to directly confront the issue of BrdU incorporation in dying versus newly reborn neurons is also very welcome, with recent studies (notably [7]) rightfully pointing out the pitfalls in blindly attributing neuronal BrdU incorporation or ectopic cell-cycle marker expression to postmitotic versus neurogenic processes. Ultimately, the vigor with which cell-cycle activation is pursued as a therapeutic target in PD will depend on the ability of cell-cycle inhibition to block neurodegeneration in vivo.

    Showing a causal connection to neurodegeneration is critical, particularly since numerous studies have shown that aberrant postmitotic neuronal cell-cycle marker expression, aneuploidy, and DNA replication can occur in vivo in the absence of neurodegeneration (for example, [2,8,9]). In this paper, Höglinger et al. use genetic reagents to specifically target cell-cycle mediators, a more convincing approach than using pharmacologic cyclin-dependent kinase inhibitors that have multiple non-cell-cycle targets (10). The authors utilize antisense to E2F-1 to convincingly protect against MPP+-induced neurodegeneration in vitro, and also demonstrate statistically significant protection in vivo, albeit more modest. The relative scarcity of SNc DA neurons incorporating BrdU or aberrantly expressing PCNA in the in vivo neurotoxic model also leaves open the question of how pervasive cell-cycle activation is as a mechanism of MPP+-induced neurodegeneration in vivo, particularly since a previous study also showed only a modest protective benefit of cell-cycle inhibition (in that case, dominant-negative Cdk2) against MPP+-induced neurotoxicity in vivo.

    Nevertheless, taken together, these data convincingly argue that cell-cycle activation should be considered seriously as a mechanism of neurodegeneration in PD. Future studies corroborating these data with further genetic manipulations, and in different animal models, particularly genetic models of PD including synucleinopathy, will strengthen the argument for testing cell-cycle inhibitors in clinical trials. Investigation of how the cell cycle becomes activated in PD, whether through oxidative stress, inhibition of the ubiquitin-proteasome system, or other mitogenic signaling pathways, will also be an important future direction.


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    . Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. PubMed.

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    . Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron. 2003 Mar 6;37(5):735-49. PubMed.

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  2. This interesting paper continues the series of studies suggesting that cell cycle reactivation in neurons is causally related to death. Hoeglinger and colleagues show that the injection of MPTP into mice, or the application of MPP+ to dopaminergic neurons, triggers mitotic signals and ensuing death in postmitotic neurons. These results are in agreement with other studies performed on similar experimental models of Parkinson disease (PD) (El-Khodor et al., 2003; Smith et al., 2003). The present paper by Hoeglinger et al. goes one step further, demonstrating that nuclear DNA is duplicated in nigral neurons in PD patients. This finding represents an interesting convergence with Karl Herrup’s data, which showed evidence of neuronal DNA replication in the Alzheimer disease (AD) brain (Yang et al., 2001).

    As such, Hoeglinger et al. provide another compelling piece of evidence that cell cycle reactivation is a common effector of neurodegeneration in different brain diseases. The open questions are clear. What drives neurons to divide? Amyloid-β (Aβ), tau, oxidative stress, excitotoxicity, and trophic factor deprivation are all candidates, but why should they do that? We have hypothesized that neurons require the reactivation of the cell cycle to reach the threshold for death when an insult per se is not sufficient to trigger apoptosis (Copani et al., 2001). The other way around has been suggested: cell cycle progression might be required for the activation of DNA repair mechanisms that eliminate neurons loaded with unrepaired DNA damage (Kruman et al., 2004).

    What is it about the reactivation of the cell cycle that kills neurons? In the case of Aβ toxicity, we have shown that the DNA replication machinery itself triggers cell death. Neurons overexpress the DNA repair enzyme DNA polymerase-β, which strangely enough has a causal role in Aβ-induced neuronal DNA replication and death (Copani et al., 2002; Copani et al., 2006). Hoeglinger’s data indicate that there is a temporal dissociation between DNA replication and neuronal death in PD patients, and the same has been found in the AD brain (Yang et al., 2001). Given the long survival of aneuploid neurons, Yang and Herrup have suggested the fascinating hypothesis that the DNA replication we observe is a protective response of stressed neurons that might benefit from having multiple allele copies (Yang et al., 2006). Even so, the final result of the neuronal cycle may be the death of the cell. Quite surprisingly, it appears that an efficient base excision repair process allows DNA replication induced by Aβ to proceed up to the threshold for death (Copani et al., 2006). Hence, whether and when a neuron dies may depend on concerted DNA replication and repair events. Certainly the paper by Hoeglinger and coworkers, together with the bulk of work preceding it, makes the case that mitotic reactivation is instrumental to neuronal death in many brain diseases.


    . Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta. Exp Neurol. 2003 Jan;179(1):17-27. PubMed.

    . Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13650-5. PubMed.

    . DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001 Apr 15;21(8):2661-8. PubMed.

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    . Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004 Feb 19;41(4):549-61. PubMed.

    . Erratic expression of DNA polymerases by beta-amyloid causes neuronal death. FASEB J. 2002 Dec;16(14):2006-8. PubMed.

    . DNA polymerase-beta is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid. J Neurosci. 2006 Oct 25;26(43):10949-57. PubMed.

    . Cell division in the CNS: protective response or lethal event in post-mitotic neurons?. Biochim Biophys Acta. 2007 Apr;1772(4):457-66. PubMed.

  3. This paper merits attention because it provides compelling evidence for the activation of cell cycle-related events in dopamine neurons of the substantia nigra, one of the principal neuronal populations to degenerate in Parkinson disease (PD), in postmortem human brain. In addition, in this comprehensive study, the investigators provide convincing evidence of a functional role for cell cycle events in mediating neuron death in two regimens of the widely used MPTP model of PD.

    The concept that cell cycle-related events play a role in programmed cell death in neurons has a long history (see, e.g., Ferrari and Greene, 1994; Freeman et al., 1994). The disease-related significance of this concept has received the greatest attention in the investigation of Alzheimer disease, where postmortem studies have demonstrated evidence of aberrant re-expression of cell cycle markers and DNA replication (see, e.g., Yang et al., 2001, recently reviewed by Neve and McPhie, 2006).

    However, this concept has received relatively little attention in the investigation of PD, other than correlative observations in rodent animal models (El-Khodor et al., 2003) and preliminary investigations in human postmortem brain (Jordan-Sciutto et al., 2003).

    This study by Hoglinger and colleagues has therefore taken a major step toward establishing the relevance of cell cycle dysregulation to neurodegeneration in PD. The importance of their work is that it establishes cell cycle mediators as potential therapeutic targets in the development of neuroprotective strategies for this disease.

    One disappointing, although not entirely unexpected, outcome of their studies is that protection from MPTP-induced dopamine neuron death in E2F-1 null mice was not accompanied by any protection of dopaminergic axonal projections to the target striatum. This result is yet another example of how an inhibition of the pathways involved in programmed cell death, which lead to the destruction of the neuron soma, does not result in a comparable protection of axonal projections. This result, and others like it, emphasize the theme that the molecular mediators of programmed axonal destruction are different from those of programmed cell death, and that they also need to be targeted by neuroprotective strategies in order to provide a meaningful benefit in the clinic.


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    . Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta. Exp Neurol. 2003 Jan;179(1):17-27. PubMed.

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  4. It's interesting that the authors report cell cycle-like mechanisms operating in PD brain tissue. I refer to my comment suggesting a role for reduced PIN1 activity and consequently reduced ability to protect Emi1 from degradation in AD. Emi1 (anaphase-promoting complex early mitotic inhibitor 1) is essential for prevention of rereplication. Ryo and colleagues (1) report that PIN1 accumulates in Lewy bodies and facilitates formation of α-synuclein inclusions. Would this also affect Emi1 degradation?

    (1) Ryo A, Togo T, Nakai T, Hirai A, Nishi M, Yamaguchi A, Suzuki K, Hirayasu Y, Kobayashi H, Perrem K, Liou YC, Aoki I. Prolyl-isomerase Pin1 accumulates in lewy bodies of parkinson disease and facilitates formation of alpha-synuclein inclusions. J Biol Chem. 2006 Feb 17;281(7):4117-25. Epub 2005 Dec 19. Abstract


    . Prolyl-isomerase Pin1 accumulates in lewy bodies of parkinson disease and facilitates formation of alpha-synuclein inclusions. J Biol Chem. 2006 Feb 17;281(7) Epub 2005 Dec 19 PubMed.

This paper appears in the following:


  1. San Diego: What Goes Around Comes Around—Cell Cycle in Postmitotic Neurons