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Transmiterea glutamatergică la nivelul sistemul nervos central.

(a) O sinapsa glutamatergică în condi ii fiziologice normale. Glutamat este eliberat deț

la nivelul termina iilor nervoase presinaptice i difuzează în fanta sinaptică. Acestaț ș

ac ionează pe mai mul i receptori ai glutamatului de pe neuronul postsinaptic.ț ț

 Ac iunea glutamatului în fantă este terminată de recaptarea sa rapidă prin intermediulț

proteinelor glutamat transportator. EAAT1 i EAAT sunt e!primate pe celulele gliale"ș

EAAT# este e!primat asupra motoneuronilor presinaptici. EAAT este responsabilpentru recaptarea glutamatului în creierul uman. $n condi ii fiziologice normaleț

activarea postsinaptică a receptorilor glutamatului are ca rezultat o u oară cre tere aș ș

calciului intracelular care poate fi tamponat în celulă.

(b) O sinapsa glutamatergică în condi ii de e!citoto!icitate. %&nd e!cesul de glutamatț

este prezent' e!istă o cre tere mare a calciului intracelular postsinaptic. Acestaș

declan ează productia mitocondriala al speciilor reactive de o!igen (O)' care apoiș

in*iba func ia EAAT gliale. Acest lucru duce la cre terea concentra iilor glutamatuluiț ș ț

 în s+napse i ridică în continuare nivelul calciului postsinaptic.ș

Figure 2. ,ailure in ascorbic acid *omeostasis contributes to neurodegeneration. -euronalT%A (tricarbo!+lic acid) and o!idative p*osp*or+lation are *ig*l+ efficient mec*anisms insustaining s+naptic activit+. o/ever' t*e continued use of o!+gen generates reactive o!+genspecies (O)' /*ic* leads to o!idative stress. T*erefore' neuronal metabolism and s+napticsignalling induce O production. -eurons are *ig*l+ sensitive to o!idative stress and t*usascorbic acid rec+cling b+ astroc+tes and neuronal upta0e t*roug* %T transporters areimportant mec*anisms in maintaining antio!idant defence. 2uring aging as /ell as inneurodegenerative diseases t*ere is an imbalance in O production' decreased levels ofantio!idant molecules and impairment in deto!if+ing enz+me activit+ suc* as supero!idedismutase (O2) or catalase. 3n 2' accumulation of mutant untingtin protein altersmitoc*ondrial biogenesis and e!pression of antio!idant defence genes' increasing o!idativedamage leading to neuronal deat*. Am+loid 4 peptide and 56s+nuclein accumulation in A2and 72 respectivel+' induce O production /*ic* in turn participates in protein aggregationand neuronal deat* in bot* pat*ologies. O21 loss of function due to its mutation isresponsible for elevated O and causal for a t+pe of A8. Ascorbic acid levels tend to bereduced in A2' A8' 2 and 72. 3n 2' /e *ave demonstrated t*at t*e failure in astroc+ticascorbic acid release and a decreased neuronal upta0e' due to t*e reduced traffic0ing of%T and G89T# transporters to t*e cell surface' are responsible for t*e impairedmetabolic s/itc*' t*e decreased neuronal antio!idant protection and most li0el+ 2metabolic failure and neuronal deat*. A26Alz*eimer:s 2isease" A86Am+otrop*ic lateralsclerosis" untington:s disease62" 7ar0inson:s 2isease672" mtt6mutant *untingtin"mO26mutant supero!ide dismutase" O26upero!ide dismutase" O6reactive o!+genspecies.

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 eents cause other correlated detrimental

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effects as the formation of misfolded protein leading to insoluble cytosolic and mitochondrial

aggregates, impaired a!onal transport and alteration of the en"ymatic actiity of #$I. %he line

 bet&een cause and effect of indiidual eents is ho&eer often difficult to dra& since they are all

tightly dependent/connected. Red arro&s may be considered as primary causes, grey arro&s as

secondary causes/effects.