xov xwm

Txawm hais tias tsis tshua muaj, qhov tshwm sim tag nrho ntawm lysosomal cia yog kwv yees li 1 ntawm txhua 5,000 tus menyuam yug los. Tsis tas li ntawd, ntawm ze li ntawm 70 paub txog lysosomal cia mob, 70% cuam tshuam rau hauv nruab nrab paj hlwb. Cov kab mob ib leeg no ua rau lysosomal tsis ua haujlwm, ua rau cov metabolism tsis ruaj khov, ua kom tsis muaj zog ntawm cov tsiaj txhu lub hom phiaj protein ntawm rapamycin (mTOR, uas ib txwm inhibits o), impaired autophagy, thiab paj hlwb tuag. Ntau qhov kev kho mob tsom rau cov txheej txheem pathologic hauv qab ntawm cov kab mob lysosomal khaws cia tau pom zoo lossis tab tom txhim kho, suav nrog enzyme hloov kho, kho substrate txo qis, kev kho molecular chaperone, kho noob, kho noob, thiab kho neuroprotective.

Niemann-pick kab mob hom C yog ib qho lysosomal cia cellular cholesterol thauj cov teeb meem tshwm sim los ntawm kev hloov pauv biallelic hauv NPC1 (95%) lossis NPC2 (5%). Cov tsos mob ntawm hom C ntawm Niemann-Pick tus kab mob muaj xws li sai, tuag taus neurological poob rau me nyuam mos, thaum lub sij hawm lig me nyuam yaus, menyuam yaus, thiab cov neeg laus pib cov ntaub ntawv muaj xws li splenomegaly, supranuclear gaze tuag tes tuag taw thiab cerebellar ataxia, dysarticulationia, thiab kev loj hlob dementia.

Hauv qhov teeb meem no ntawm phau ntawv journal, Bremova-Ertl thiab al qhia cov txiaj ntsig ntawm ob qhov muag tsis pom kev, tswj cov placebo, kev sib tw sib tw. Qhov kev sim tau siv cov tshuaj tiv thaiv kab mob neuroprotective, cov amino acid analogue N-acetyl-L-leucine (NALL), los kho Niemann-Pick kab mob hom C. Lawv nrhiav 60 cov tsos mob ntawm cov tub ntxhais hluas thiab cov neeg laus thiab cov txiaj ntsig tau pom muaj kev txhim kho tseem ceeb hauv tag nrho cov qhab nia (qhov kawg ntawm qhov tseem ceeb) ntawm Ataxia Kev Ntsuas thiab Kev Ntsuas Ntsuas.

Cov kev sim tshuaj ntawm N-acetyl-DL-leucine (Tanganil), ib haiv neeg ntawm NALL thiab n-acetyl-D-leucine, zoo li tau tsav los ntawm kev paub ntau: cov txheej txheem ntawm kev ua haujlwm tsis tau qhia meej meej. N-acetyl-dl-leucine tau txais kev pom zoo rau kev kho mob ntawm tus mob vertigo txij li xyoo 1950; Tsiaj qauv qhia tias cov tshuaj ua haujlwm los ntawm kev sib npaug ntawm overpolarization thiab depolarization ntawm medial vestibular neurons. Tom qab ntawd, Strupp et al. tau tshaj tawm cov txiaj ntsig ntawm kev tshawb fawb luv luv uas lawv tau pom kev txhim kho cov tsos mob hauv 13 cov neeg mob uas muaj degenerative cerebellar ataxia ntawm ntau yam etiologies, kev tshawb pom uas ua rau muaj kev txaus siab los saib cov tshuaj dua.

Lub tshuab uas n-acetyl-DL-leucine txhim kho cov paj hlwb tseem tsis tau paub meej, tab sis qhov kev tshawb pom hauv ob tus qauv nas, ib qho ntawm Niemann-Pick kab mob hom C thiab lwm yam ntawm GM2 ganglioside cia teeb meem Variant O (Sandhoff disease), lwm tus kab mob neurodegenerative lysosomal, tau ua rau muaj kev xav tig mus rau NALL. Tshwj xeeb, kev ciaj sia ntawm Npc1-/- nas kho nrog n-acetyl-DL-leucine los yog NALL (L-enantiomers) zoo dua, thaum muaj sia nyob ntawm cov nas kho nrog n-acetyl-D-leucine (D-enantiomers) tsis tau, qhia tias NALL yog daim ntawv nquag ntawm cov tshuaj. Hauv kev tshawb fawb zoo sib xws ntawm GM2 ganglioside cia tsis sib haum O (Hexb-/-), n-acetyl-DL-leucine tau ua rau muaj kev sib haum xeeb tab sis tseem ceeb txuas ntxiv ntawm kev ua neej nyob hauv nas.

Txhawm rau tshawb nrhiav cov txheej txheem ntawm kev ua ntawm n-acetyl-DL-leucine, cov kws tshawb fawb tau tshawb xyuas txoj hauv kev metabolic ntawm leucine los ntawm kev ntsuas cov metabolites hauv cov ntaub so ntswg cerebellar ntawm cov tsiaj mutant. Hauv kev hloov pauv O tus qauv ntawm GM2 ganglioside cia teeb meem, n-acetyl-DL-leucine normalizes qabzib thiab glutamate metabolism, nce autophagy, thiab nce qib ntawm superoxide dismutase (ib qho kev nqus pa oxygen). Hauv C qauv ntawm Niemann-Pick kab mob, kev hloov pauv hauv qabzib thiab antioxidant metabolism thiab kev txhim kho hauv mitochondrial zog metabolism tau pom. Txawm hais tias L-leucine yog lub zog mTOR activator, tsis muaj kev hloov pauv hauv qib lossis phosphorylation ntawm mTOR tom qab kho nrog n-acetyl-DL-leucine lossis nws cov enantiomers hauv tus qauv nas.

Cov nyhuv neuroprotective ntawm NALL tau pom nyob rau hauv tus qauv nas ntawm cortical impingement induced hlwb raug mob. Cov teebmeem no suav nrog txo qis cov cim neuroinflammatory, txo qis cortical cell tuag, thiab txhim kho autophagy flux. Tom qab kev kho NALL, lub cev muaj zog thiab kev paub txog kev ua haujlwm ntawm cov nas raug mob tau rov qab los thiab qhov mob loj zuj zus.

Cov lus teb inflammatory ntawm lub hauv nruab nrab lub paj hlwb yog cov cim ntawm feem ntau neurodegenerative lysosomal cia mob. Yog tias neuroinflammation tuaj yeem txo qis nrog NALL kev kho mob, cov tsos mob ntawm ntau, yog tias tsis yog tag nrho, neurodegenerative lysosomal storage disorders tuaj yeem txhim kho. Raws li txoj kev tshawb no qhia, NALL tseem xav tias yuav muaj kev sib koom ua ke nrog lwm cov kev kho mob rau cov kab mob lysosomal cia.

Ntau yam lysosomal cia mob kuj tseem cuam tshuam nrog cerebellar ataxia. Raws li kev tshawb fawb thoob ntiaj teb nrog rau cov menyuam yaus thiab cov neeg laus uas muaj GM2 ganglioside cia mob (Tay-Sachs kab mob thiab Sandhoff kab mob), ataxia tau txo qis thiab kev sib koom ua ke ntawm lub cev muaj zog zoo dua tom qab kho NALL. Txawm li cas los xij, qhov loj, multicenter, ob-dig muag, randomized, placebo-tswj sim tau pom tias n-acetyl-DL-leucine tsis tau kho zoo rau cov neeg mob uas muaj kev sib xyaw ua ke (kuj, tsis tau txais txiaj ntsig, thiab tsis piav qhia) cerebellar ataxia. Qhov kev tshawb pom no qhia tias kev ua tau zoo tsuas yog pom nyob rau hauv kev sim nrog cov neeg mob uas muaj cov kab mob cerebellar ataxia thiab cov txheej txheem cuam tshuam ntawm kev soj ntsuam. Tsis tas li ntawd, vim tias NALL txo qis neuroinflamation, uas tuaj yeem ua rau mob hlwb raug mob, kev sim ntawm NALL rau kev kho mob ntawm lub hlwb raug mob yuav raug txiav txim siab.