Transmiterea glutamatergic la nivelul sistemul nervos central.

(a) O sinapsa glutamatergic n condiii fiziologice normale. Glutamat este eliberat de

la nivelul terminaiilor nervoase presinaptice i difuzeaz n fanta sinaptic. Acesta
acioneaz pe mai muli receptori ai glutamatului de pe neuronul postsinaptic.
Aciunea glutamatului n fant este terminat de recaptarea sa rapid prin intermediul
proteinelor glutamat transportator. EAAT1 i EAAT2 sunt exprimate pe celulele gliale;
EAAT3 este exprimat asupra motoneuronilor presinaptici. EAAT2 este responsabil
pentru recaptarea glutamatului n creierul uman. n condi ii fiziologice normale
activarea postsinaptic a receptorilor glutamatului are ca rezultat o u oar cre tere a
calciului intracelular care poate fi tamponat n celul.
(b) O sinapsa glutamatergic n condiii de excitotoxicitate. Cnd excesul de glutamat
este prezent, exist o cretere mare a calciului intracelular postsinaptic. Acesta
declaneaz productia mitocondriala al speciilor reactive de oxigen (ROS), care apoi
inhiba funcia EAAT2 gliale. Acest lucru duce la cre terea concentra iilor glutamatului
n synapse i ridic n continuare nivelul calciului postsinaptic.
Figure 2. Failure in ascorbic acid homeostasis contributes to neurodegeneration. Neuronal
TCA (tricarboxylic acid) and oxidative phosphorylation are highly efficient mechanisms in
sustaining synaptic activity. However, the continued use of oxygen generates reactive oxygen
species (ROS), which leads to oxidative stress. Therefore, neuronal metabolism and synaptic
signalling induce ROS production. Neurons are highly sensitive to oxidative stress and thus
ascorbic acid recycling by astrocytes and neuronal uptake through SVCT2 transporters are
important mechanisms in maintaining antioxidant defence. During aging as well as in
neurodegenerative diseases there is an imbalance in ROS production, decreased levels of
antioxidant molecules and impairment in detoxifying enzyme activity such as superoxide
dismutase (SOD) or catalase. In HD, accumulation of mutant Huntingtin protein alters
mitochondrial biogenesis and expression of antioxidant defence genes, increasing oxidative
damage leading to neuronal death. Amyloid peptide and -synuclein accumulation in AD
and PD respectively, induce ROS production which in turn participates in protein aggregation
and neuronal death in both pathologies. SOD1 loss of function due to its mutation is
responsible for elevated ROS and causal for a type of ALS. Ascorbic acid levels tend to be
reduced in AD, ALS, HD and PD. In HD, we have demonstrated that the failure in astrocytic
ascorbic acid release and a decreased neuronal uptake, due to the reduced trafficking of
SVCT2 and GLUT3 transporters to the cell surface, are responsible for the impaired
metabolic switch, the decreased neuronal antioxidant protection and most likely HD
metabolic failure and neuronal death. AD-Alzheimers Disease; ALS-Amyotrophic lateral
sclerosis; Huntingtons disease-HD; Parkinsons Disease-PD; mHtt-mutant huntingtin;
mSOD-mutant superoxide dismutase; SOD-Superoxide dismutase; ROS-reactive oxygen
species.

Figure 1. Mitochondrial dysfunction and oxidative stress (OS) are tightly dependent
on each other and are the basis of the redox dysregulation in ALS. Increased
production of ROS/RNS, the ER stress and, at least in part, transcriptional dysregulation and
abnormal RNA processing are all consequences of mitochondrial dysfunction and OS contributing

to death of motor neurons. In turn, these pathological events cause other correlated detrimental
effects as the formation of misfolded protein leading to insoluble cytosolic and mitochondrial
aggregates, impaired axonal transport and alteration of the enzymatic activity of PDI. The line
between cause and effect of individual events is however often difficult to draw since they are all
tightly dependent/connected. Red arrows may be considered as primary causes, grey arrows as
secondary causes/effects.