Rideout HJ, Wang Q, Park DS, Stefanis L.
Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition.
J Neurosci. 2003 Feb 15;23(4):1237-45.
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It has been known for some time that abnormalities of the proteasome system occur in neurons in several neurodegenerative disorders, including Alzheimer’s disease (AD) and Lewy body (LB) diseases. While a number of proteasome abnormalities have been described in these diseases, little has been published about the mechanistic implications of these abnormalities. It has been shown experimentally that proteasome inhibitors can cause apoptosis of postmitotic neurons, but the pathway by which this apoptosis occurs remains incompletely described. Thus, this paper by Rideout and colleagues is a major step forward in understanding how proteasome abnormalities might cause neurodegeneration.
The authors tie together two disparate lines of research on neurodegenerative diseases: the one showing dysfunction of the proteasome in these disorders and the one showing aberrant cell-cycle activation in some of the same disorders, most notably AD. Rideout et al. show convincingly and elegantly that aberrant activation of cyclin-dependent kinases (Cdks) that act at the G1-to-S phase of the cell cycle is required for proteasomal inhibition-induced apoptosis of primary cortical neurons. The work is remarkable in using not only pharmacological inhibitors, but also expression of specific genes that inhibit Cdks and expression of dominant-negative Cdks, to show the participation of Cdk2, Cdk4, and Cdk6 in the apoptosis. The results are also notable in their agreement with two recent papers from Karl Herrup’s group, in which it is shown that cell-cycle aberrations precede neuronal cell death in AD brain (Yang et al., 2003; Yang et al., 2001).
Rideout and colleagues also demonstrate that cyclins D1 and E translocate to the nucleus and accumulate in ubiquitinated inclusions in neurons in which the proteasome is inhibited pharmacologically. In this regard, our laboratory has reported that increases in the levels of the AβPP-interacting protein AβPP-BP1 can also cause neuronal apoptosis (Chen et al., 2000). Interestingly, AβPP-BP1, which is elevated in AD brain (unpublished data from our laboratory), initiates a ubiquitin-like pathway that interfaces with the ubiquitin pathway to cause accumulation of cyclin E. It is exciting to anticipate that the literatures on proteasomal dysfunction, cell-cycle dysfunction, and AβPP dysfunction in neurodegenerative diseases may be beginning to converge.
Yang Y, Mufson EJ, Herrup K.
Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease.
J Neurosci. 2003 Apr 1;23(7):2557-63.
Yang Y, Geldmacher DS, Herrup K.
DNA replication precedes neuronal cell death in Alzheimer's disease.
J Neurosci. 2001 Apr 15;21(8):2661-8.
Chen Y, McPhie DL, Hirschberg J, Neve RL.
The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons.
J Biol Chem. 2000 Mar 24;275(12):8929-35.
This is an excellent study that delineates the precise role of cdks in neuronal death using a combination of pharmacological and molecular tools. It is particularly interesting that both the proteasome and cdks are obligatory mediators of apoptosis, but that cdks are not involved in formation of ubiquitin-protein inclusions. In a sense, these results support previous suggestions that inclusions are a byproduct of degeneration, but are not necessary for neuronal death.
While there is no doubt that neurons die independently of lesion formation in many different diseases, it is hard to imagine that the presence of a cytoplasmic or nuclear inclusion would not disrupt normal cellular processes, and eventually promote death. Nevertheless, studies such as this one, which elucidate the temporal and spatial relationships between various death markers, are crucial in designing appropriate targets for treating neurodegenerative diseases.
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