Научная статья на тему 'Defining the role of ciliary proteins BBS (Bardet-Biedl syndrome) in neuroplasticity'

Defining the role of ciliary proteins BBS (Bardet-Biedl syndrome) in neuroplasticity Текст научной статьи по специальности «Фундаментальная медицина»

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Текст научной работы на тему «Defining the role of ciliary proteins BBS (Bardet-Biedl syndrome) in neuroplasticity»

Section MOLECULAR NEUROSCIENCE Aims

The closely related neuronal bHLH transcription factors Neurod1, Neurod2 and Neurod6 are expressed by differentiating pyramidal neurons in the developing cere-bral cortex and have long been suspected to regulate the maturation of these cells. Each of the three genes was genetically inactivated in mice, but studies of single-deficient animals failed to identify important functions in embryonic pyramidal neu-rons. High sequence similarity and overlapping expression patterns suggest func-tional redundancy. We used double and triple deficient mice to identify NeuroD-family dependent functions and downstream molecular mechanisms.

Methods

We bred Neurod2/6 double-deficient and Neurod1/2/6 triple deficient mice and analyzed cerebral cortex development with an emphasis on pyramidal neuron identity and neocortical connectivity. We use in situ hybridization to visualize and in utero electroporation to manipulate the expression of possible target genes in the cerebral cortex.

Results

Neurod2 and Neurod6 indeed share several hitherto unknown functions and compensate for each other's loss. At least one of the two genes is necessary for: (1) the control of radial migration in a subset of pyramidal neurons; (2) area determination in the neocortex; and (3) the formation of fiber tracts connecting the neocortex to the striatum, to the thalamus, and to the contralateral hemisphere. In Neurod2/6 double-deficient mice, callosal axons form fasciculated fiber bundles that grow tan-gentially into the medial neocortex, but stall and defasciculate before reaching the ipsilateral cingulum or any midline associated structure. This new variant of callosal agenesis implies the presence of a so far identified axon guidance mechanism in the medial neocortex. We present EphrinA signaling as possible mechanism. Neurod1 shares additional functions with Neurod2 and Neurod6. At least one of the three genes is necessary for hippocampal pyramidal neuron differentiation and the prevention of developmental cell death in the medial cortex. While the simulta-neous inactivation of Neurod1/2/6 results in the complete loss of archicortical pyramidal neurons, many neocortical pyramidal cells survive, migrate radially and settle in the cortical plate. However, terminal pyramidal neuron differentiation is incomplete and neocortical connectivity is dramatically reduced in triple-deficient mice.

Conclusion

NeuroD-family transcription factors cooperatively regulate pyramidal neuron differentiation, survival, migration, specification and axon growth in the developing cerebral cortex.

References

1. I. Bormuth et al., J Neurosci., 2013, 33(2), 641-51.

Defining the Role of Ciliary Proteins BBS (Bardet-Biedl Syndrome) in Neuroplasticity

Sophia Christou-Savina*

London's Global University, UK. * Presenting e-mail: s.christou-savina@ucl.ac.uk

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, autosomal recessive disorder characterised by early-onset retinal degeneration, obesity, polydactyly, and renal malformation/dysfunction. It affects approximately 1:100,000 people in Northern Europe reaching 1:13,500 in more isolated populations. More than half of all individuals with BBS also experience developmental disabilities ranging from mild learning impairment to severe mental retardation independent of gene mutation. Many patients display obsessive/compulsive tendencies and a preference for fixed routines and 37% of children attending our national BBS clinics have autism spectrum disorder. Poor memory and cognition in Bardet-Biedl syndrome lead to inability to live independently and few are in employment (9%).

OM&P

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: mnlabspb@gmail.com

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: mnlabspb@gmail.com

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