Gaba
2
Transmiterea glutamatergică la nivelul sistemul nervos central. (a) O sinapsa glutamatergică în c ondi ii fiziologice normale. Glutamat este eliberat de ț la nivelul termina iilor nervoase presinaptice i difuz ează în fa nta s inaptică. Acesta ț ș ac ione ază pe mai mul i recepto ri ai glutamatu lui de pe neuronu l postsina ptic. ț ț Ac iunea glutamatului în fantă este terminată de recaptarea sa rapidă prin intermediul ț proteinelor glutamat transportator. EAAT1 i EAAT su nt e!primate pe c elulele gliale" ș EAAT # este e!primat asupra motoneuronilor presinaptici. EAAT este responsabil pentru recaptarea glutamatului în creieru l uman. $n condi ii fiziologice normale ț activ area p ostsi naptic ă a rec eptorilor glutama tului are ca rezultat o u oară cre tere a ș ș calciului intracelular care poate fi tamponat în celulă. (b) O sinapsa glutamatergic ă în condi ii de e!citoto!icitate. %&nd e!c esul de glutamat ț este prezent' e!istă o cre tere mare a calciului intrace lular postsinaptic. Acesta ș declan ează productia mitocondriala al speciilor reactive de o!igen (O)' care a poi ș in*i ba func ia EAA T g liale. Ac est luc ru duc e la cre terea concentra iilor glu tamatu lui ț ș ț în s+napse i ridică în continuare nivelul calciului postsinaptic. ș Figure 2. ,ailure in ascorbic acid *omeostasis contributes to neurodegeneration. -euronal T%A (tricarbo!+ lic acid) and o!idative p*osp*or+lation are *ig*l+ efficient mec*anisms in sustaining s+naptic activit+. o/ever' t*e continued use of o!+gen generates reactive o!+gen species (O)' /*ic* leads to o!idative stress. T*erefore' neuronal metabolism and s+naptic signallin g induce O production. -eurons are *ig*l+ sensitive to o!idative stress and t*us ascorbic acid rec+cling b+ astroc+tes and neuronal upta0e t*roug* %T transporters are important mec*anisms in maintaining antio!idant defence. 2uring aging as /ell as in neurodegenerative diseases t*ere is an imbalance in O production' decreased levels of antio!idan t molecules and impairment in deto!if+ing enz+me activit+ suc* as supero!ide dismutase (O2) or catalase. 3n 2' accumulatio n of mutant untingtin protein alters mitoc*ondrial biogenesis and e!pression of antio!idant defence genes' increasing o!idative damage leading to neuronal deat*. Am+loid 4 peptide and 56s+nuclein accumulation in A2 and 72 respectivel+' induce O production /*ic* in turn participates in protein aggregation and neuronal deat* in bot* pat*ologies. O21 loss of function due to its mutation is responsible for elevated O and causal for a t+pe of A8. Ascorbic acid levels tend to be reduced in A2' A8' 2 and 72. 3n 2' /e *ave demonstrated t*at t*e failure in astroc+tic ascorbic 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 impaired metabolic s/itc*' t*e decreased neuronal antio!idant protection and most li0el+ 2 metabolic failure and neuronal deat*. A26Alz*eimer:s 2isease" A86Am+otrop*ic lateral sclerosis" untington:s disease62" 7ar0inson:s 2isease672" mtt6mutant *untingtin" mO26mutant supero!ide dismutase" O26upero!ide dismutase" O6reactive o!+gen 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 c ontributing to death of motor neurons. In turn, these pathological eents cause other correlated detrimental
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Transcript of Gaba
7/21/2019 Gaba
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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
7/21/2019 Gaba
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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.
