**Part 3**

**Cellular Pathophysiology, the Immune System and Stem Cell Strategies** 

374 Amyotrophic Lateral Sclerosis

Ting, K. K. (2008). Quinolinic acid and its effect on the astrocyte with relevance to the

Vidic-Dankovic, B., D. Kosec*, et al.* (1995). Leflunomide prevents the development of experimentally induced myasthenia gravis. *Int J Immunopharmacol* 17(4): 273-81. Vigh, L., R. G. Smith*, et al.* (2005). Sublethal dose of 4-hydroxynonenal reduces intracellular calcium in surviving motor neurons in vivo. *Acta Neuropathol* 109(6): 567-75. Werner-Felmayer, G., E. R. Werner*, et al.* (1989). Characteristics of interferon induced

Williamson, R. A., C. M. Yea*, et al.* (1995). Dihydroorotate dehydrogenase is a high affinity

Wilms, H., J. Sievers*, et al.* (2003). Intrathecal synthesis of monocyte chemoattractant protein-

Wu, H. Q., S. C. Lee*, et al.* (2000). Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. *Eur J Pharmacol* 390(3): 267-74. Wu, H. Q., F. G. Salituro*, et al.* (1997). Enzyme-catalyzed production of the neuroprotective

Yamanaka, K., S. J. Chun*, et al.* (2008). Astrocytes as determinants of disease progression in

Yan, E., M. Castillo-Melendez*, et al.* (2005). Quinolinic acid promotes albumin deposition in

Yang, J. S., L. Y. Xu*, et al.* (2004). Laquinimod (ABR-215062) suppresses the development of

Zhang, H., C. Andrekopoulos*, et al.* (2003). Bicarbonate-dependent peroxidase activity of

Zou, L. P., N. Abbas*, et al.* (2002). Suppression of experimental autoimmune neuritis by

immunomodulatory compound. *J Biol Chem* 270(38): 22467-72.

activation in neurodegeneration. *J Neuroimmunol* 144(1-2): 139-42.

inherited amyotrophic lateral sclerosis. *Nat Neurosci* 11(3): 251-3.

tryptophan metabolism in human cells in vitro. *Biochim Biophys Acta* 1012(2): 140-7.

binding protein for A77 1726 and mediator of a range of biological effects of the

1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial

NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo. *Eur J* 

Purkinje cell, astrocytic activation and lipid peroxidation in fetal brain. *Neuroscience*

experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. *J Neuroimmunol* 156(1-2): 3-9. Yasui, H., K. Takai*, et al.* (1986). Interferon enhances tryptophan metabolism by inducing

pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients.

human Cu,Zn-superoxide dismutase induces covalent aggregation of protein: intermediacy of tryptophan-derived oxidation products. *J Biol Chem* 278(26): 24078-

ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. *Neuropharmacology* 42(5): 731-9.

pathogenesis of Alzheimer's disease [Thesis].

*Pharmacol* 319(1): 13-20.

*Proc Natl Acad Sci U S A* 83(17): 6622-6.

134(3): 867-75.

89.

**16** 

*Belgium* 

**The Astrocytic Contribution in ALS:** 

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease, due to the loss of motor neurons and denervation of muscle fibres, resulting in increasing muscle weakness and paralysis. The disease has an incidence of 2.7 cases per 100,000 people in Europe (Longroscino et al., 2010). It is diagnosed from teen years onward, but is more prevalent in the later years of life. In lack of a medical cure, average life expectancy post diagnosis is between 2 and 5 years, though 10% of all patients live longer than 10 years. Patients mainly succumb to the disease by respiratory insufficiency or may opt for euthanasia where legislature permits (Maessen et al., 2010). Although ALS is characterised by degeneration of central nervous system tissue, mental functions remain largely unaffected resulting in a locked-in state (Kotchoubey et al., 2003). At current, there is but one medicine to

treat the disease, riluzole, slowing disease progression moderately (Miller et al., 2007).

Mutations in the ubiquitously expressed Cu/Zn superoxide dismutase 1 (SOD1) gene can cause ALS. SOD1 detoxifies cell damaging free radicals and its mutations account for 20% of the ALS patients suffering from the disease by familial origin (fALS) worldwide. The remaining 90% of ALS patients suffer from the disease by unknown sporadic causes (sALS), though a common mechanism is predicted as fALS and sALS patients display indistinguishable clinical phenotypes. Overexpression of mutant forms of human SOD1 causes the ALS phenotype of transgenic SOD1 mice, accounting for an invaluable contribution to ALS research (Gurney et al., 1994). Many hallmarks of the disease are shared between patients and this rodent model, including specific motor neuron loss, aggregate formation, astrogliosis, microgliosis and progressive paralysis. As the genetic ablation of SOD1 does not produce an ALS-like phenotype in mice (Reaume et al., 1996; Shefner et al., 1999) the pathogenic mechanism of mutant SOD1 is a toxic gain of function. This gain of function may be exerted by protein misfolding, aggregation, impaired proteasome functioning, impaired retrograde transport, excitotoxic cell death or other mechanisms (reviewed in Bruijn et al., 2004). Mutations in other genes also cause familial ALS, including mutations in vesicle-associated membrane proteinassociated protein B (VAPB), TAR DNA binding protein (TDP-43), fused in

**1. Introduction** 

**1.1 Basic genetics of ALS** 

**Inflammation and Excitotoxicity** 

Kim Staats1,2 and Ludo Van Den Bosch1,2

*1University of Leuven,* 

*2VIB Vesalius Research Center,* 
