Oral Presentation 2014 International Biophysics Congress

Neurobiophysics of excitotoxicity of IgGs and mSOD1 as humoral factors of amyotrophic lateral sclerosis pathophysiology (#40)

Pavle R. Andjus 1
  1. Faculty of Biology , University of Belgrade, Belgrade, Serbia

Amyotrophic lateral sclerosis (ALS) is an adult onset fatal neurodegenerative disease characterized mainly by the progressive loss of upper and lower motor neurons resulting in wasting, paresis and death from respiratory failure. Approximately 5-10% of ALS cases are familial (fALS), while the rest are sporadic (sALS) with unknown cause of disease. Driven by early studies demonstarting that transfer of purified immunoglobulins G from ALS patients (ALS IgGs) could cause the disease in mice1 we have shown that these immune factors also induce excitotoxic synaptic activity in different in vitro setups, notably not only consisting of motoneurons2,3. In light of the newly established theory that the disease is non-cell autonomous we have checked the effect of ALS IgGs on calcium homeostasis and mobility of endosomes/lysosomes in cultured rat cortical astrocytes. ALS IgGs evoked calcium transients (Ca2+-waves) in astrocytes4, the effect not requiring extracellular Ca2+. Pharmacological dissection revealed the role of inositol 1,4,5-triphosphate, phospholipase C, phosphatidilinositol-3-kinase, as well as of the transient receptor potential cation channels. On the other hand, experiments on intracellular acidic vesicles labeled with lysotracker, demonstrated that ALS IgGs increased their mobility in a Ca2+-dependent manner5. Recent data using an L-glutamate dehydrogenase based assay indicate that these ALS IgG effects are in fact underlining glutamate release from astrocytes. Another particular ALS-specific humoral factor of excitotoxicity studied by exogenous application was the mutant SOD1 –G93A (expressed in some fALS cases). In cultured astrocytes it also disrupted Ca2+ homeostasis and changed electrophysiological properties of the cell membrane. Thus, we have revealed IgGs and mSOD1 as specific humoral excitotoxic factors in ALS affecting not just neurons but non-neuronal, glial cells as well. While mSOD1 is probably released by the astrocytes themselves, IgGs can actually cross into brain parenchima through a hampered blood-brain barrier in ALS (as evidenced by our MRI studies).

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  2. Andjus PR, Khiroug L, Nistri A, Cherubini E. Neuroreport. 7:1914 (1996)
  3. Andjus PR, Stevic-Marinkovic Z, Cherubini E. J Physiol. 504 (Pt 1):103 (1997)
  4. Milošević M, Stenovec M, Kreft M, Petrušić V, Stević Z, Trkov S, Andjus PR, Zorec R. Cell Calcium. 54:17 (2013)
  5. Stenovec M, Milošević M, Petrušić V, Potokar M, Stević Z, Prebil M, Kreft M, Trkov S, Andjus PR, Zorec R. Acta Physiol (Oxf) 203:457 (2011)