Page - (000185) - in Biomedical Chemistry: Current Trends and Developments

that compromises daily activities, and brain regions involved in cognitive processes show glutamatergic impairment (Miller, 2000; Falkenberg, 2014; Plitman, 2014). The glutamatergic system is currently recognized to have a crucial role in the pathogenesis of schizophrenia (Coyle, 2012). It is proposed that hypofuncional NMDARs in inhibitory interneurons disinhibit pyramidal excitatory neurons, therefore increasing glutamate release (Moghaddam, 2012). The glutamate release will overstimulate non-NMDARs, particularly AMPARs, which will result in an excitotoxic effect related to structural features of the disease (Deutsch, 2001). Neuroanatomical changes were reported in patients, such as a loss of grey matter in several brain regions, like the cortex, thalamus and basal ganglia; whole brain volume reduction and white matter changes (Lawrie, 1998; Meyer-Lindenberg, 2011; Colibazzi, 2013). Various studies linked these neuroanatomical changes to neurodegeneration triggered by excitotoxic mechanisms, particularly related to decreased levels of glutamate in the thalamus, that will hypostimulate NMDARs in interneurons, leading to increased glutamate release in thalamocortical pathways (Theberge, 2007). Glutamate overstimulation of AMPARs will probably lead to excitotoxic increase of intracellular Ca2+ (Deutsch, 2001). Also, other studies implicated glutamate transporters EAATs in the glutamatergic dysfunction occurring in schizophrenia. Particularly, both EAAT1 and 3 where shown to be upregulated in schizophrenic patients, and the increase in EAAT3 may attenuate NMDARs function, leading to the hipo-NMDARs stimulation (Bauer, 2008; Rao, 2012). Ataxia is a deregulation of limb movements and poor coordination of the limbs. The most common ataxias are cerebellar ataxias, which are caused by a dysfunction of the cerebellum. Spinocerebellar ataxia (SCA) is caused by an abnormal function of the part of the cerebellar cortex that receives input from the spinal cord. Usually, hereditary dominant forms of SCA are progressive and fatal neurodegenerative disorders. Seven SCAs are caused by expansion of CAG-repeats in particular genes, leading to long polyglutamine sequences in the proteins translated. These polyglutamine containing proteins aggregate and form misfolded protein deposites that constitute characteristic neuronal cytoplasmic or nuclear inclusions, which are hallmarks of SCAs and are associated with