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OM&P
Section MOLECULAR NEUROSCIENCE
We and others have previously demonstrated that patients with BBS have significantly decreased hippocampal and neocortical volumes. The exact mechanisms of hippocampal dysgenesis and reduced cortex volume in BBS are not known, however, one of the plausible explanations could be a reduced neuroplasticity.
It is widely believed that adult neurogenesis as well as regulation of dendritic spine formation is an important component of neuronal plasticity. We speculated that cognitive impairment in BBS might result from impaired neuroplasticity. Using BBS knockout mice models we have shown a significant reduction in adult neurogenesis of Bbs4 and Bbs5 mice. Moreover, we have shown global reduction of dendritic spines (including the hippocampus) and discovered that the spine loss occurs within the first 3 postnatal weeks resulting from increased autophagy during this period. Most strikingly we have confirmed that the plasticity of spines can be repaired by the introduction of aerobic exercise in these mice.
Neuronal Store Operated Calcium Entry as Novel Therapetic Target for Treatment of Alzheimer's Disease
Ilya Bezprozvanny
1,2 *
1 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
2 Laboratory of Molecular Neurodegeneration, St Petersburg State Polytechnical University, St Petersburg, 195251, Russia. * Presenting e-mail: [email protected]
Memory loss in Alzheimer's disease (AD) results from "synaptic failure". Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and AD. To understand the basis for memory loss in AD we performed a series of mechanistic studies of hippocampal synap-tic spines in mouse models of familial AD (FAD). In our experiments we used presenilin 1 (PS1) M146V knockin (PS1KI) and APPKI models of FAD. In the course of these studies we discovered an existence of spine maintenance pathway that is mediated by neuronal store-operated Ca2+ entry (nSOC) in postsynaptic spines (Sun et al, 2014). We established that nSOC pathway plays a key role in stability of mushroom spines by constitutively activating synap-tic CaMKII kinase. We further demonstrated that synaptic nSOC is controlled by stromal interaction molecule 2 (STIM2) and that STIM2-nSOC-CaMKII pathway is compromised in PS1KI and APPKI neurons, in aging neurons and in sporadic AD brains due to downregulation of STIM2 protein (Sun et al., 2014; Zhang at al 2015). Moreover, we have demonstrated that expression of STIM2 protein rescues synaptic nSOC and mushroom spine loss in PS1KI and APPKI hippocampal neurons (Sun et al., 2014; Zhang at al 2015) and protects mushroom spines from amyloid synaptotoxicity (Popugaeva at al, 2015). These studies suggested that STIM2-nSOC pathway is a potentially important AD therapeutic target, and that activators and positive modulators of this pathway may have a utility for treatment of synaptic loss and memory decline in aging and AD.
References
1. Suya Sun, Hua Zhang, Jie Liu, Elena Popugaeva, Nan-Jie Xu, Stefan Feske, Charles L. White, III, and Ilya Bezprozvanny (2014) Reduced Synaptic STIM2 Expression and Impaired Store-Operated Calcium Entry Cause Destabilization of Mature Spines in Mutant Presenilin Mice. Neuron, vol 82, pp 79-93.
2. Elena Popugaeva, Ekaterina Pchitskaya, Anastasiya Speshilova, Sergey Alexandrov, Hua Zhang, Olga Vlasova, Ilya Bezprozvanny (2015) STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Molecular Neurodegeneration, 10:37.
3. Hua Zhang, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Takashi Saito, Takaomi Saido and Ilya Bezprozvanny (2015) Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer's disease. J. Neuroscience, vol 35, pp 13275-13286.
The 2.2-Angstrom Resolution Crystal Structure of the Carboxy-terminal Region of Ataxin-3
Ilya Bezprozvanny
1,2
1 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
2 Laboratory of Molecular Neurodegeneration, St Petersburg State Polytechnical University, St Petersburg, 195251, Russia. * Presenting e-mail: [email protected]
20 Opera Med Physiol 2016 Vol. 2 (S1)
