. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature. 2006 Jun 29;441(7097):1144-8. PubMed.

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  1. Time for the Ubiquitin-Proteasome System #2: Dendritic Spines
    Synaptic dysfunction and loss are likely to coincide with mild cognitive impairments and Alzheimer disease (Terry et al., 1991). This idea was later confirmed by many other groups (e.g., Selkoe, 2002). In this paper by Bingol and Schuman, much in vitro evidence is shown for activity-dependent dynamics and sequestration of proteasomes. These authors report NMDA receptor-dependent redistribution of proteasome subunits (e.g., of triple A proteins of the 19S regulatory particles; AAA = ATPases Associated with a variety of cellular Activities) from dendritic shafts to synaptic spines by an active process (via actin) upon synaptic stimulation. This provides a mechanism for local protein degradation by the ubiquitin-proteasome system. Interestingly, one of the triple A proteins used is Rpt3 or proteasome subunit 6b (with a chaperone-like activity), which has been found in neurofibrillary tangles of Alzheimer disease, suggesting a role for this subunit in AD (Fergusson et al., 1996). The next step would be to validate these results in vivo. A transgenic mouse model of the ubiquitin-proteasome system is available (Lindsten et al., 2003). Two-photon in vivo imaging is now possible (Holtmaat et al., 2006). Moreover, attractive, multiple Alzheimer models are available that may enable the link to Alzheimer disease (Oddo et al., 2003). In crossbreeds of these mouse lines, a study of recruitment of proteasomes from dendritic shafts to spines after NMDA receptor activation may yield very interesting data.

    References:

    . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80. PubMed.

    . Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PubMed.

    . Pathological lesions of Alzheimer's disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26S proteasome. Neurosci Lett. 1996 Nov 29;219(3):167-70. PubMed.

    . A transgenic mouse model of the ubiquitin/proteasome system. Nat Biotechnol. 2003 Aug;21(8):897-902. PubMed.

    . Experience-dependent and cell-type-specific spine growth in the neocortex. Nature. 2006 Jun 22;441(7096):979-83. PubMed.

    . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.

  2. This study represents a fascinating example of the increasingly recognized role of the proteasome in hitherto unappreciated functions. The authors convincingly show that there is redistribution of the proteasome from dendritic shafts to spines and synaptosomes following NMDA receptor stimulation. Moreover, this redistribution has functional consequences, as demonstrated by increased clearance of substrates of the ubiquitin-proteasome system. The authors show that the redistribution of the proteasome is related to a tighter contact with the actin cytoskeleton within the spines. They suggest that the observed redistribution of the proteasomes may play a functional role in the sculpting of synaptic transmission, by changing the local microenvironment. Notably, the observed proteasomal redistribution significantly outlasted the stimulation period, suggesting that the changes conferred may be quite long-lasting. Although a functional effect of proteasomal redistribution on synaptic transmission is not proven in this manuscript, this study provides a convincing argument for the importance of the dynamics of proteasomal localization in this setting. This study may be important in the context of neurodegeneration, where proteasomal dysfunction is thought to occur. Thus, altered function or dynamics of proteasomal localization may lead to dysfunctional neurotransmission, which is now widely thought to precede neuronal death in neurodegenerative diseases.

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