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The Journal of Neuroscience, October 1, 2003, 23(26)
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This Week in the Journal
Cellular/Molecular
Inclusion Bodies and Proteasomes
Proteasome Inhibition Stabilizes Tau Inclusions in Oligodendroglial Cells which Occur after Treatment with Okadaic Acid
Olaf Goldbaum, Malte Oppermann, Melanie Handschuh, Deepa Dabir, Bin Zhang, Mark S. Forman, John Q. Trojanowski, Virginia M.-Y. Lee, and Christiane Richter-Landsberg
(see pages 8872-8880)
Fine Structure and Biochemical Mechanisms Underlying Nigrostriatal Inclusions and Cell Death after Proteasome Inhibition
Francesco Fornai, Paola Lenzi, Marco Gesi, Michela Ferrucci, Gloria Lazzeri, Carla L. Busceti, Riccardo Ruffoli, Paola Soldani, Stefano Ruggieri, Maria G. Alessandrì, and Antonio Paparelli
(see pages 8955-8966)
The ubiquitin-proteasome (UP) system tags and degrades misfolded proteins, thus preventing formation of protein aggregates that can lead to cell death. Two papers in this week's Journal focus on the role of the UP system in neurological disease. Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by inclusion bodies containing the filamentous protein tau. In AD, tau accumulates in neurons, whereas in other "tauopathies," tau inclusions also occur in glia. Goldbaum et al. created a glial cell line that overexpresses tau. Hyperphosphorylated, transient tau aggregates could be detected in these cells, but stable aggregates were seen only after proteasome inhibition. In the second report, Fornai et al. injected UP inhibitors into the striatum and observed selective neurotoxicity of dopamine neurons in the substantia nigra, the region affected in PD. By manipulating cytosolic dopamine, they found that the neurotransmitter itself underlies the cellular selectivity. These reports hint at proteasome dysfunction as a contributor to several neurodegenerative diseases.
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OLN-t40 cells, treated with 20 nM okadaic acid for 6 hr, show thioflavin-S-positive aggregates (green). Nuclei were stained with 4',6'-diamidino-2-phenylindole (DAPI; blue), and tau was stained with anti-tau antibodies (red). See Figure 4 of Goldbaum et al. for details.
Development/Plasticity/Repair
Region-Specific Trophic Support of Motoneurons
Cardiotrophin-Like Cytokine/Cytokine-Like Factor 1 Is an Essential Trophic Factor for Lumbar and Facial Motoneurons In Vivo
Nancy G. Forger, David Prevette, Odile deLapeyri
re, Béatrice de Bovis, Siwei Wang, Perry Bartlett, and Ronald W. Oppenheim
(see pages 8854-8858)
Approximately one-half of spinal and cranial motoneurons undergo programmed cell death during embryonic development. Motoneuron survival depends on several trophic factors, including a trimeric complex known as the ciliary neurotrophic factor (CNTF) receptor. However, deletion of CNTF itself does not impair survival, and CNTF is essentially absent during the period of developmental cell death. In this issue, Forger et al. explore a proposed ligand for the CNTF receptor: a heterodimer formed by cardiotrophin-like cytokine (CLC) with cytokine-like factor 1 (CLF). CLC/CLF can be secreted and is known to form a complex with the CNTF receptor. Forger et al. found that exogenous CLC increased survival of embryonic chick motoneurons, whereas deletion of clf resulted in depletion of motoneurons. Interestingly, the susceptibility was region specific, because only lumbar motoneurons of the spinal cord and facial of the brainstem were affected by these manipulations. Brachial, thoracic, and hypoglossal motoneurons as well as sensory neurons were unaffected. The authors detected mRNA for both clc and clf in skeletal muscle fibers; thus the CLC/CLF heterodimer appears to be target derived. Why the interaction of CLC/CLF with the CNTF receptor is region specific remains a question.
Behavioral/Systems/Cognitive
Desynchronizing the Reticular Thalamus
Inhibitory Interconnections Control Burst Pattern and Emergent Network Synchrony in Reticular Thalamus
Vikaas S. Sohal and John R. Huguenard
(see pages 8978-8988)
The spike-wave discharge (SWD) of absence ("petit mal") epilepsy, one of the most distinctive of all EEG patterns, has long been attributed to thalamocortical (TC) circuits. Normal thalamocortical oscillations such as sleep spindles can be converted into SWD by blocking inhibition in the thalamic reticular (RE) nucleus. This basis of this behavior resides in intrinsic thalamic circuitry, including interconnections between inhibitory RE cells and their reciprocal connections with TC relay neurons. In this circuit, RE-driven cyclical inhibition of TC cells produces rebound excitation controlled by low-threshold calcium spikes and subsequent re-excitation of RE cells. In this issue, Sohal and Huguenard recorded from oscillating RE neurons in thalamic slices to assess the function of intra-RE inhibition. When GABAA receptors were blocked, RE cells showed synchronized bursts of activity. As expected, intact inhibition prevented SWD, but it did so by limiting the number of bursts rather than their duration. The block of occasional bursts effectively desynchronized the network, a finding supported by the authors' network simulations. As a result, TC cell activity can be switched from the low-amplitude irregular oscillations characteristic of spindles to the high-amplitude epileptiform-like oscillations of the SWD.
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