Nakuba kuyivelakancane, isigameko sisonke sokugcinwa kwe-lysosomal cishe si-1 kuzo zonke izingane ezizalwa eziphilayo ezingu-5,000. Ngaphezu kwalokho, ezinkingeni zokugcinwa kwe-lysosomal ezingaba ngu-70 ezaziwayo, ama-70% athinta isimiso sezinzwa esimaphakathi. Lokhu kuphazamiseka kofuzo olulodwa kubangela ukungasebenzi kahle kwe-lysosomal, okuholela ekungameni kahle kwezinqubo ze-metabolic, ukungasebenzi kahle kwephrotheni eqondiwe ezincelisayo ye-rapamycin (mTOR, evamise ukuvimbela ukuvuvukala), ukukhubazeka kwe-autophagy, nokufa kwamangqamuzana ezinzwa. Izindlela zokwelapha eziningana eziqondise ezindleleni eziyisisekelo ze-pathologic zesifo sokugcina i-lysosomal zivunyelwe noma zisathuthukiswa, okuhlanganisa ukwelashwa kokubuyisela i-enzyme, ukwelapha okuncishiswa kwe-substrate, ukwelapha nge-molecular chaperone, ukwelashwa kwezakhi zofuzo, ukuhlela izakhi zofuzo, kanye nokwelashwa nge-neuroprotective.
Isifo se-Niemann-pick uhlobo C isifo sokuthutha se-lysosomal esibangelwa ukuguqulwa kwe-biallelic ku-NPC1 (95%) noma i-NPC2 (5%). Izimpawu zohlobo C lwesifo i-Niemann-Pick zihlanganisa ukwehla okusheshayo, okubulalayo kwezinzwa ebuntwaneni, kuyilapho amafomu okuqala kwengane esephuzile, eyentsha, kanye neyabantu abadala ahlanganisa i-splenomegaly, i-supranuclear gaze paralysis kanye ne-cerebellar ataxia, i-dysarticulationia, kanye nokuwohloka komqondo okuqhubekayo.
Kulolu shicilelo lwejenali, i-Bremova-Ertl et al babika imiphumela yesivivinyo esingaboni kabili, esilawulwa yi-placebo, nesiphambano. Ukuhlolwa kwasebenzisa i-ejenti ye-neuroprotective engase ibe khona, i-amino acid analogue N-acetyl-L-leucine (NALL), ukwelapha uhlobo lwesifo se-Niemann-Pick C. Baqasha iziguli ezingu-60 ezinezimpawu zentsha kanye nabantu abadala futhi imiphumela yabonisa ukuthuthukiswa okuphawulekayo kumaphuzu aphelele (iphoyinti lokugcina eliyinhloko) le-Ataxia Assessment and Rating Scale.
Izivivinyo zomtholampilo ze-N-acetyl-DL-leucine (Tanganil), i-racemic ye-NALL kanye ne-n-acetyl-D-leucine, kubonakala sengathi iqhutshwa kakhulu isipiliyoni: indlela yokwenza ayikacaciswanga ngokucacile. I-N-acetyl-dl-leucine igunyazwe ukwelashwa kwe-acute vertigo kusukela ngawo-1950; Amamodeli ezilwane aphakamisa ukuthi umuthi usebenza ngokulinganisa kabusha i-overpolarization kanye ne-depolarization ye-medial vestibular neurons. Kamuva, u-Strupp et al. ibike imiphumela yocwaningo lwesikhashana lapho bebona khona ukuthuthukiswa kwezimpawu ezigulini ze-13 ezine-cerebellar ataxia ewohlokayo ye-etiologies ehlukahlukene, okutholakele okwavuselela isithakazelo ekubukeni umuthi futhi.
Indlela i-n-acetyl-DL-leucine ethuthukisa ngayo ukusebenza kwezinzwa ayikacaci, kodwa okutholwe kumamodeli amabili wamagundane, eyodwa ye-Niemann-Pick yesifo sohlobo C kanye nesinye se-GM2 ganglioside storage disorder Variant O (isifo se-Sandhoff), esinye isifo se-neurodegenerative lysosomal, kuye kwabangela ukunakwa kokuphendukela ku-NALL. Ngokukhethekile, ukusinda kwamagundane e-Npc1-/- aphathwe nge-n-acetyl-DL-leucine noma i-NALL (L-enantiomers) kwaba ngcono, kuyilapho ukusinda kwamagundane aphathwe nge-n-acetyl-D-leucine (D-enantiomers) akuzange kube ngcono, okuphakamisa ukuthi i-NALL iwuhlobo olusebenzayo lomuthi. Ocwaningweni olufanayo lwe-GM2 ganglioside storage disorder variant O (Hexb-/-), i-n-acetyl-DL-leucine iholele ekwandiseni okunesizotha kodwa okubalulekile kwesikhathi sokuphila kumagundane.
Ukuhlola indlela yokusebenza ye-n-acetyl-DL-leucine, abacwaningi baphenye indlela ye-metabolic ye-leucine ngokulinganisa ama-metabolites ezicutshini ze-cerebellar zezilwane eziguquguqukayo. Kumodeli ye-O ehlukile ye-GM2 ganglioside storage disorder, i-n-acetyl-DL-leucine yenza kujwayelekile i-glucose ne-glutamate metabolism, ikhuphule i-autophagy, futhi ikhuphule amazinga e-superoxide dismutase (i-scavger yomoya-mpilo esebenzayo). Kumodeli ye-C yesifo sika-Niemann-Pick, izinguquko ku-glucose kanye ne-antioxidant metabolism kanye nokuthuthukiswa kwe-mitochondrial energy metabolism kwabonwa. Nakuba i-L-leucine iyisicuphi se-mTOR esinamandla, akubangakho uguquko kuzinga noma i-phosphorylation ye-mTOR ngemva kokwelashwa nge-n-acetyl-DL-leucine noma ama-enantiomers ayo kunoma iyiphi imodeli yegundane.
Umthelela we-neuroprotective we-NALL ubonwe kumodeli yegundane yokulimala kobuchopho okudalwe yi-cortical. Le miphumela ihlanganisa ukwehlisa izimpawu ze-neuroinflammatory, ukunciphisa ukufa kwamangqamuzana e-cortical, nokuthuthukisa i-autophagy flux. Ngemuva kokwelashwa kwe-NALL, imisebenzi ye-motor kanye neyomqondo yamagundane alimele yabuyiselwa futhi nosayizi wesilonda wehliswa.
Ukusabela kokuvuvukala kwesimiso sezinzwa esimaphakathi kuwuphawu lwezinkinga eziningi ze-neurodegenerative lysosomal storage. Uma i-neuroinflammation ingancishiswa ngokwelashwa kwe-NALL, izimpawu zomtholampilo zabaningi, uma kungezona zonke, ukuphazamiseka kwe-neurodegenerative lysosomal storage kungase kuthuthukiswe. Njengoba lolu cwaningo lubonisa, i-NALL kulindeleke futhi ukuthi ibe nokusebenzisana nezinye izindlela zokwelapha isifo se-lysosomal storage.
Izinkinga eziningi zokugcina i-lysosomal nazo zihlotshaniswa ne-cerebellar ataxia. Ngokocwaningo lwamazwe ngamazwe oluhilela izingane kanye nabantu abadala abanezinkinga zokugcinwa kwe-GM2 ganglioside (isifo sika-Tay-Sachs nesifo sika-Sandhoff), i-ataxia yehliswa futhi nokuxhumana kahle kwezimoto kwaba ngcono ngemva kokwelashwa kwe-NALL. Kodwa-ke, ucwaningo olukhulu, oluningi, oluyimpumputhe oluphindwe kabili, olungahleliwe, olulawulwa yi-placebo lubonise ukuthi i-n-acetyl-DL-leucine yayingasebenzi kahle emtholampilo ezigulini ezine-cerebellar ataxia exubile (ezuzwe njengefa, engeyona ifa, futhi engachazwanga). Lokhu kutholakala kuphakamisa ukuthi ukusebenza kahle kungabonwa kuphela ezivivinyweni ezibandakanya iziguli ezine-cerebellar ataxia ezizuzwe njengefa kanye nezindlela ezihambisanayo zokwenza izinto ezihlaziywayo. Ukwengeza, ngenxa yokuthi i-NALL inciphisa i-neuroinflammation, engaholela ekulimazeni okubuhlungu kobuchopho, ukuhlolwa kwe-NALL kokwelashwa kokulimala kobuchopho okubuhlungu kungase kucatshangelwe.
Isikhathi sokuthumela: Mar-02-2024