Astrocyte degeneration in Amyotrophic Lateral Sclerosis: mechanism and rescue
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1
IRCCS Fondazione Salvatore Maugeri, Centre for Molecular Medicine, Italy
A major constraint to the comprehension of the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) has been long represented by the conviction that this disorder selectively affects motor neurons in a cell-autonomous manner. However, the failure to identify the events underlying the neurodegenerative process and the increased knowledge of the complex cellular interactions necessary for the correct functioning of the CNS has recently focused the attention on the contribution to neurodegeneration of glial cells, including astrocytes. Astrocytes can hurt motor neurons by secreting neurotoxic factors, but they can also play a deleterious role by losing functions that are supportive for neurons.
Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1G93A mouse model of ALS. Mechanistic studies in vitro identified a role for the transmitter glutamate in the gliodegenerative process via the activation of its inositol 1,4,5 triphosphate (IP3)-generating metabotropic receptor 5 (mGluR5).
Since non-physiological formation of IP3 can prompt IP3 receptor (IP3R)-mediated Ca2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca2+ signalling that occurs downstream of mGluR5 in hSOD1G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca2+ concentrations in the absence of spontaneous oscillations. The interaction of IP3Rs with the anti-apoptotic protein Bcl-XL was previously described to prevent cell death by modulating intracellular Ca2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-XL, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1G93A mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays disease onset, and improves both motor performance and survival.
Keywords:
Amyotrophic Lateral Sclerosis,
astrocyte,
Glutamate,
Calcium,
Bcl-XL
Conference:
4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Türkiye, 30 Sep - 3 Oct, 2012.
Presentation Type:
Symposium
Topic:
Abstracts
Citation:
Rossi
D
(2013). Astrocyte degeneration in Amyotrophic Lateral Sclerosis: mechanism and rescue
.
Conference Abstract:
4th Conference of the Mediterrarnean Neuroscience Society.
doi: 10.3389/conf.fnhum.2013.210.00061
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Received:
28 Jan 2013;
Published Online:
11 Apr 2013.
*
Correspondence:
Dr. Daniela Rossi, IRCCS Fondazione Salvatore Maugeri, Centre for Molecular Medicine, Pavia, 27100, Italy, daniela.rossi@icsmaugeri.it