amakuru

Nubwo ari gake cyane, muri rusange ububiko bwa lysosomal bugera kuri 1 kuri 5.000 bavutse ari bazima. Byongeye kandi, mubibazo bigera kuri 70 bizwi byo kubika lysosomal, 70% bigira ingaruka kuri sisitemu yo hagati. Izi ndwara ziterwa na gene imwe itera imikorere mibi ya lysosomal, bikaviramo guhungabana kwa metabolike, kugabanuka kwa poroteyine y’inyamabere y’inyamabere ya rapamycine (mTOR, ubusanzwe ibuza gucana), kwangirika kwa autophagy, no gupfa kwingirangingo. Ubuvuzi butandukanye bwibanda ku buryo bw’ibanze bw’indwara ya lysosomal bwemejwe cyangwa burimo gutezwa imbere, harimo kuvura insimburangingo ya enzyme, kugabanya insimburangingo, kuvura molekile ya chaperone, kuvura gene, gutunganya gene, hamwe n’ubuvuzi bwa neuroprotective

Indwara ya Niemann-C ni ubwoko bwa lysosomal ububiko bwa selile cholesterol itwara iterwa no guhinduka kwa biallelic haba muri NPC1 (95%) cyangwa NPC2 (5%). Ibimenyetso byubwoko bwa C bwindwara ya Niemann-Pick harimo kugabanuka byihuse, byica neurologiya bikabije bikiri uruhinja, mugihe abana batinze, abana bato, nabakuze batangiye harimo splenomegaly, paralise gaze paralise na cerebellar ataxia, dysarticulationia, hamwe no guta umutwe.

Muri iyi nimero yikinyamakuru, Bremova-Ertl et al raporo y'ibyavuye mu rubanza rwahumye-impumyi ebyiri, rugenzurwa na platbo, rwambukiranya imipaka. Ikigeragezo cyakoresheje uburyo bwa neuroprotective agent, amino aside analogue N-acetyl-L-leucine (NALL), kugirango bavure ubwoko bwindwara ya Niemann-Pick C. Binjije abarwayi 60 bangavu nibimenyetso byabakuze kandi ibisubizo byagaragaje iterambere ryinshi mumanota yose (iherezo ryambere) ryisuzuma rya Ataxia.

Igeragezwa rya clinique ya N-acetyl-DL-leucine (Tanganil), ubwoko bwa NALL na n-acetyl-D-leucine, bisa nkaho biterwa ahanini nuburambe: uburyo bwibikorwa ntabwo bwasobanuwe neza. N-acetyl-dl-leucine yemerewe kuvura vertigo ikaze kuva 1950; Icyitegererezo cy’inyamaswa cyerekana ko imiti ikora mu kongera guhuza polarisiyonike no gutandukana kwa neuron yo hagati. Ibikurikira, Strupp n'abandi. yatangaje ibyavuye mu bushakashatsi bwakozwe mu gihe gito aho bagaragaje iterambere ry’ibimenyetso ku barwayi 13 barwaye cerebellar ataxia yangirika ya etiologiya zitandukanye, ubushakashatsi bwagaragaje ubushake bwo kongera kureba ibiyobyabwenge.

Uburyo n-acetyl-DL-leucine iteza imbere imikorere yimitsi ntabwo irasobanuka neza, ariko ibyagaragaye muburyo bubiri bwimbeba, imwe yindwara ya Niemann-Pick yo mu bwoko bwa C nubundi bwa GM2 ganglioside yibibazo byo kubika Variant O (Indwara ya Sandhoff), indi ndwara ya lysosomal neurodegenerative lysosomal, yatumye abantu bitabaza NALL. By'umwihariko, kubaho kwa Npc1 - / - imbeba zavuwe na n-acetyl-DL-leucine cyangwa NALL (L-enantiomers) byateye imbere, mu gihe ubuzima bw’imbeba zavuwe na n-acetyl-D-leucine (D-enantiomers) butabikoze, byerekana ko NALL ari uburyo bukomeye bw’ibiyobyabwenge. Mu bushakashatsi busa na GM2 ganglioside yo guhunika ububiko bwa O (Hexb - / -), n-acetyl-DL-leucine yatumye ubuzima bwiyongera mu buryo bworoheje ariko bukomeye mu mbeba.

Kugira ngo hamenyekane uburyo bwo gukora n-acetyl-DL-leucine, abashakashatsi bakoze ubushakashatsi ku nzira ya metabolike ya leucine bapima metabolite mu ngingo z’ubwonko bw’inyamaswa zahinduwe. Muburyo bwa O moderi ya GM2 ganglioside ihungabana, n-acetyl-DL-leucine isanzwe glucose na glutamate metabolism, ikongera autophagy, kandi ikongera urugero rwa superoxide (scavger ikora). Mu cyitegererezo C cy’indwara ya Niemann-Pick, hagaragaye impinduka muri glucose na metabolisme ya antioxydeant ndetse no kunoza ingufu za mitochondial metabolism. Nubwo L-leucine ikora cyane ya mTOR, nta cyahindutse murwego cyangwa fosifora ya mTOR nyuma yo kuvurwa na n-acetyl-DL-leucine cyangwa enantiomers yayo muburyo bwimbeba.

Ingaruka ya neuroprotective ya NALL yagaragaye muburyo bwimbeba ya cortical impingement iterwa no gukomeretsa ubwonko. Izi ngaruka zirimo kugabanya ibimenyetso bya neuroinflammatory, kugabanya urupfu rwa cortical selile, no kuzamura autophagy flux. Nyuma yo kuvura NALL, imikorere ya moteri nubwenge yimbeba zakomeretse zaragaruwe kandi ingano yangirika iragabanuka.

Igisubizo cya inflammatory ya santrale yo hagati nicyo kiranga indwara nyinshi zo mu bwoko bwa lysosomal. Niba neuroinflammation ishobora kugabanuka hamwe no kuvura NALL, ibimenyetso byubuvuzi bya benshi, niba atari byose, indwara ya neurodegenerative lysosomal ihungabana irashobora kunozwa. Nkuko ubu bushakashatsi bubyerekana, NALL nayo iteganijwe kugira imikoranire nubundi buryo bwo kuvura indwara ya lysosomal.

Ububiko bwinshi bwa lysosomal nabwo bufitanye isano na cerebellar ataxia. Nk’uko ubushakashatsi mpuzamahanga bwerekeranye n’abana ndetse n’abantu bakuru bafite ikibazo cyo kubika GM2 ganglioside (indwara ya Tay-Sachs n’indwara ya Sandhoff), ataxia yagabanutse kandi guhuza ibinyabiziga neza nyuma yo kuvurwa NALL. Nyamara, igeragezwa rinini, ryinshi, rihumye-impumyi, riteganijwe, rigenzurwa na platbo ryerekanye ko n-acetyl-DL-leucine itagize ingaruka nziza mubuvuzi ku barwayi bafite imvange (yarazwe, itarazwe, kandi idasobanutse) cerebellar ataxia. Ubu bushakashatsi bwerekana ko imikorere ishobora kugaragara gusa mu bigeragezo bireba abarwayi bafite ubwonko bwa cerebellar ataxia hamwe nuburyo bujyanye n’ibikorwa byasesenguwe. Byongeye kandi, kubera ko NALL igabanya neuroinflammation, ishobora gukomeretsa ubwonko bwubwonko, hashobora gutekerezwa ibizamini bya NALL byo kuvura ibikomere byubwonko.