iindaba

Nangona kunqabile ngokwentelekiso, izehlo ezipheleleyo zokugcinwa kwe-lysosomal malunga ne-1 kwi-5,000 yokuzalwa okuphilayo. Ukongeza, malunga ne-70 eyaziwayo yokuphazamiseka kokugcinwa kwe-lysosomal, i-70% ichaphazela inkqubo ye-nervous central. Oku kuphazamiseka kwemfuza enye kubangela ukungasebenzi kakuhle kwe-lysosomal, okukhokelela ekungazinzini kwe-metabolic, ukungasebenzi kakuhle kweprotein ekujoliswe kuyo ye-mammalian ye-rapamycin (i-mTOR, ehlala inqanda ukudumba), ukukhubazeka kwe-autophagy, kunye nokufa kwe-nerve cell. Unyango oluninzi olujolise kwiindlela ezisisiseko ze-pathologic yesifo sogcino lwe-lysosomal zamkelwe okanye ziphantsi kophuhliso, kubandakanywa unyango lokubuyisela i-enzyme, unyango lokunciphisa i-substrate, unyango lwe-molecular chaperone, unyango lwemfuza, ukuhlelwa kofuzo, kunye nonyango lwe-neuroprotective.

I-Niemann-pick isifo sohlobo C yi-lysosomal yokugcina i-cholesterol yeselula yokuthutha ukuphazamiseka okubangelwa ukuguqulwa kwe-biallelic kwi-NPC1 (95%) okanye i-NPC2 (5%). Iimpawu zohlobo C lwesifo i-Niemann-Pick ziquka ukwehla ngokukhawuleza, okubulalayo kwemithambo-luvo ebuntwaneni, ngelixa abantwana abasemva kwexesha, abancinci, kunye neefom zokuqala zibandakanya i-splenomegaly, i-supranuclear gaze paralysis kunye ne-cerebellar ataxia, i-dysarticulationia, kunye ne-dementia eqhubekayo.

Kulo mbandela wephephancwadi, i-Bremova-Ertl et al ibika iziphumo ze-double blind-blind, placebo-controlled, trial crossover. Ulingo lusebenzise i-agent ye-neuroprotective enokubakho, i-amino acid analogue N-acetyl-L-leucine (NALL), ukunyanga isifo se-Niemann-Pick uhlobo C. Baye baqesha i-60 yeempawu ze-adolescent kunye nezigulane zabantu abadala kwaye iziphumo zibonise ukuphuculwa okuphawulekayo kumanqaku apheleleyo (isiphelo sokuqala) soVavanyo lwe-Ataxia kunye neSikali sokulinganisa.

Izilingo zeklinikhi ze-N-acetyl-DL-leucine (Tanganil), i-racemic ye-NALL kunye ne-n-acetyl-D-leucine, ibonakala iqhutywe kakhulu ngamava: indlela yokusebenza ayizange icaciswe ngokucacileyo. I-N-acetyl-dl-leucine ivunyiwe unyango lwe-vertigo enzima ukususela kwi-1950; Iimodeli zezilwanyana zibonisa ukuba iyeza lisebenza ngokulungelelanisa i-overpolarization kunye ne-depolarization ye-medial vestibular neurons. Emva koko, uStrupp et al. ingxelo iziphumo zophononongo lwexesha elifutshane apho babona ukuphuculwa kweempawu kwizigulane ze-13 ezine-cerebellar ataxia ephazamisayo ye-etiologies eyahlukeneyo, iziphumo eziye zalawula umdla ekujongeni ichiza kwakhona.

Indlela apho i-n-acetyl-DL-leucine iphucula umsebenzi we-nerve ayikacaci, kodwa ukufunyaniswa kwiimodeli ezimbini zegundane, enye ye-Niemann-Pick yesifo sohlobo C kunye nenye ye-GM2 ganglioside storage disorder Variant O (isifo se-Sandhoff), esinye isifo se-neurodegenerative lysosomal, siye sabangela ukuba ingqalelo iphendukele kwi-NALL. Ngokukodwa, ukusinda kwe-Npc1-/- iigundane eziphathwe nge-n-acetyl-DL-leucine okanye i-NALL (L-enantiomers) kuphuculwe, ngelixa ukusinda kweempuku eziphathwa nge-n-acetyl-D-leucine (D-enantiomers) azange, ebonisa ukuba i-NALL yindlela esebenzayo yeyeza. Kuphononongo olufanayo lwe-GM2 ye-ganglioside yokugcina ukuphazamiseka kwe-O (Hexb-/-), i-n-acetyl-DL-leucine ibangele ukongezwa okuthobekileyo kodwa okubalulekileyo kwexesha lokuphila kwiimpuku.

Ukuphonononga indlela yokusebenza kwe-n-acetyl-DL-leucine, abaphandi baphanda indlela ye-metabolic ye-leucine ngokulinganisa i-metabolites kwizicubu ze-cerebellar zezilwanyana eziguqukayo. Kwimo ehlukile ye-O ye-GM2 ye-ganglioside yokugcina i-disorder, i-n-acetyl-DL-leucine ilungisa i-glucose kunye ne-glutamate metabolism, yandisa i-autophagy, kwaye yandisa amanqanaba e-superoxide dismutase (i-oxygen scavger esebenzayo). Kwimodeli ye-C ye-Niemann-Pick isifo, utshintsho kwi-glucose kunye ne-antioxidant metabolism kunye nokuphuculwa kwe-mitochondrial energy metabolism yabonwa. Nangona i-L-leucine i-activator ye-mTOR enamandla, akukho tshintsho kwinqanaba okanye i-phosphorylation ye-mTOR emva konyango nge-n-acetyl-DL-leucine okanye i-enantiomers yayo nayiphi na imodeli yegundane.

Impembelelo ye-neuroprotective ye-NALL iye yabonwa kwimodeli yemouse ye-cortical impingement eyenzelwe ukulimala kwengqondo. Ezi ziphumo ziquka ukunciphisa iimpawu ze-neuroinflammatory, ukunciphisa ukufa kweeseli ze-cortical, kunye nokuphucula i-autophagy flux. Emva konyango lwe-NALL, i-motor kunye nemisebenzi yengqondo yeempuku ezonzakeleyo zabuyiselwa kwaye ubungakanani bokulimala buncitshisiwe.

Impendulo yokuvuvukala kwenkqubo ye-nervous central luphawu lweengxaki ezininzi ze-neurodegenerative lysosomal storage. Ukuba i-neuroinflammation inokwehliswa ngonyango lwe-NALL, iimpawu zeklinikhi zabaninzi, ukuba azikho zonke, ukuphazamiseka kwe-neurodegenerative lysosomal storage kungaphuculwa. Njengoko olu phononongo lubonisa, i-NALL ilindeleke ukuba ibe nentsebenziswano kunye nolunye unyango lwesifo sokugcina i-lysosomal.

Uninzi lweengxaki zokugcina i-lysosomal nazo zihambelana ne-cerebellar ataxia. Ngokophononongo lwamazwe ngamazwe olubandakanya abantwana kunye nabantu abadala abane-GM2 ye-ganglioside yokugcina ukuphazamiseka (isifo se-Tay-Sachs kunye nesifo se-Sandhoff), i-ataxia yancitshiswa kwaye ukulungelelaniswa kakuhle kwemoto kuphuculwe emva konyango lwe-NALL. Nangona kunjalo, uvavanyo olukhulu, olubanzi, oluyimfama oluphindwe kabini, olungenamkhethe, olulawulwa yi-placebo lubonise ukuba i-n-acetyl-DL-leucine ayizange isebenze ngokweklinikhi kwizigulane ezixubeneyo (ezizuzwe njengefa, ezingekho, kunye nezingachazwanga) i-cerebellar ataxia. Olu phando lubonisa ukuba ukuphumelela kunokubonwa kuphela kwizilingo ezibandakanya izigulane ezine-cerebellar ataxia ezizuzwe njengelifa kunye neendlela ezinxulumene nazo zokuhlalutya. Ukongezelela, ngenxa yokuba i-NALL inciphisa i-neuroinflammation, enokubangela ukulimala kwengqondo ebuhlungu, iimvavanyo ze-NALL zonyango lokulimala kwengqondo okubuhlungu kunokuqwalaselwa.