nkhani

Ngakhale ndizosowa, kuchuluka kwa lysosomal kusungirako kumakhala pafupifupi 1 mwa obadwa 5,000 aliwonse. Kuphatikiza apo, mwa pafupifupi 70 omwe amadziwika kuti lysosomal storage disorders, 70% amakhudza dongosolo lapakati lamanjenje. Matenda amtundu umodziwa amayambitsa kusagwira bwino ntchito kwa lysosomal, zomwe zimapangitsa kusakhazikika kwa kagayidwe kachakudya, kusokonekera kwa mapuloteni amtundu wa rapamycin (mTOR, omwe nthawi zambiri amaletsa kutupa), kuwonongeka kwa autophagy, ndi kufa kwa mitsempha. Njira zingapo zochiritsira zomwe zimayang'ana njira zomwe zimayambitsa matenda a lysosomal storage zavomerezedwa kapena zikupangidwa, kuphatikiza ma enzyme replacement therapy, substrate reduction therapy, molecular chaperone therapy, gene therapy, gene editing, ndi neuroprotective therapy.

Niemann-pick matenda amtundu wa C ndi matenda a lysosomal osungira ma cell cholesterol obwera chifukwa cha kusintha kwa biallelic mu NPC1 (95%) kapena NPC2 (5%). Zizindikiro za mtundu C wa matenda a Niemann-Pick zimaphatikizapo kutsika kofulumira, koopsa kwa minyewa akadali wakhanda, pomwe mawonekedwe ochedwa achichepere, achichepere, ndi achikulire amaphatikizapo splenomegaly, supranuclear gaze paralysis ndi cerebellar ataxia, dysarticulationia, ndi dementia wopita patsogolo.

M'magazini ino ya magazini, Bremova-Ertl et al akufotokoza zotsatira za mayesero awiri akhungu, oyendetsedwa ndi placebo, crossover. Mlanduwu unagwiritsa ntchito mankhwala omwe amatha kugwiritsira ntchito neuroprotective, amino acid analogue N-acetyl-L-leucine (NALL), kuti athetse matenda a Niemann-Pick mtundu C. Iwo adalemba 60 zizindikiro zaunyamata ndi odwala akuluakulu ndipo zotsatira zake zinawonetsa kusintha kwakukulu kwa chiwerengero chonse (mapeto oyambirira) a Ataxia Assessment and Rating Scale.

Mayesero azachipatala a N-acetyl-DL-leucine (Tanganil), mpikisano wa NALL ndi n-acetyl-D-leucine, akuwoneka kuti amayendetsedwa kwambiri ndi zomwe zachitika: njira yochitirapo sinafotokozedwe momveka bwino. N-acetyl-dl-leucine yavomerezedwa kuti ichiritse vertigo pachimake kuyambira 1950s; Zitsanzo za zinyama zimasonyeza kuti mankhwalawa amagwira ntchito pogwirizanitsa kuwonjezereka kwapadera ndi kusokoneza ma neurons a medial vestibular. Pambuyo pake, Strupp et al. lipoti zotsatira za kafukufuku yochepa imene iwo anaona kusintha kwa zizindikiro 13 odwala ndi osachiritsika cerebellar ataxia zosiyanasiyana etiologies, anapeza kuti analamuliranso chidwi kuyang'ana mankhwala kachiwiri.

Njira yomwe n-acetyl-DL-leucine imathandizira kugwira ntchito kwa minyewa sikudziwika bwino, koma zomwe zapezeka mumitundu iwiri ya mbewa, imodzi mwa matenda a Niemann-Pick mtundu C ndi ina ya GM2 ganglioside storage disorder Variant O (matenda a Sandhoff), matenda ena a neurodegenerative lysosomal, apangitsa chidwi kutembenukira ku NALL. Mwachindunji, kupulumuka kwa mbewa za Npc1-/- zothandizidwa ndi n-acetyl-DL-leucine kapena NALL (L-enantiomers) zinayenda bwino, pamene kupulumuka kwa mbewa zothandizidwa ndi n-acetyl-D-leucine (D-enantiomers) sikunatero, kutanthauza kuti NALL ndi mawonekedwe a mankhwala. Mu kafukufuku wofanana wa GM2 ganglioside storage disorder variant O (Hexb-/-), n-acetyl-DL-leucine inachititsa kuti moyo ukhale wocheperapo koma wofunikira wa mbewa.

Kuti afufuze momwe n-acetyl-DL-leucine imagwirira ntchito, ofufuzawo adafufuza njira ya kagayidwe kachakudya ya leucine poyesa metabolites mu minyewa ya cerebellar ya nyama zosinthika. Mu mtundu wosiyana wa O wa GM2 ganglioside storage disorder, n-acetyl-DL-leucine imapangitsa shuga ndi glutamate metabolism kukhala yokhazikika, imawonjezera autophagy, ndikuwonjezera milingo ya superoxide dismutase (yoyaka oxygen scavger). Muchitsanzo cha C cha matenda a Niemann-Pick, kusintha kwa glucose ndi antioxidant metabolism komanso kusintha kwa kagayidwe ka mphamvu ya mitochondrial kunawonedwa. Ngakhale L-leucine ndi activator yamphamvu ya mTOR, panalibe kusintha kwa mlingo kapena phosphorylation ya mTOR pambuyo pa chithandizo ndi n-acetyl-DL-leucine kapena enantiomers mu chitsanzo cha mbewa.

Mphamvu ya neuroprotective ya NALL yawonedwa mumtundu wa mbewa wa cortical impingement yochititsa kuvulala kwaubongo. Zotsatirazi zikuphatikiza kutsitsa zolembera za neuroinflammatory, kuchepetsa kufa kwa ma cortical cell, ndikuwongolera kusinthasintha kwa autophagy. Pambuyo pa chithandizo cha NALL, magalimoto ndi chidziwitso cha mbewa zovulala zinabwezeretsedwa ndipo kukula kwa zilonda kunachepetsedwa.

Kuyankha kotupa kwa dongosolo lapakati lamanjenje ndiye chizindikiro chazovuta zambiri za neurodegenerative lysosomal storage. Ngati neuroinflammation ingachepetsedwe ndi chithandizo cha NALL, zizindikiro zachipatala za ambiri, ngati si onse, matenda a neurodegenerative lysosomal storage akhoza kusintha. Monga momwe kafukufukuyu akusonyezera, NALL ikuyembekezekanso kukhala ndi mgwirizano ndi njira zina zochizira matenda a lysosomal storage.

Mavuto ambiri osungira lysosomal amalumikizidwanso ndi cerebellar ataxia. Malinga ndi kafukufuku wapadziko lonse lapansi wokhudza ana ndi akulu omwe ali ndi vuto la GM2 ganglioside storage (matenda a Tay-Sachs ndi matenda a Sandhoff), ataxia idachepetsedwa ndipo kulumikizana kwabwino kwamagalimoto kunakula pambuyo pa chithandizo cha NALL. Komabe, kafukufuku wamkulu, wamitundu yambiri, wakhungu, wakhungu, wosasinthika, woyesedwa ndi placebo adawonetsa kuti n-acetyl-DL-leucine sinali yothandiza pachipatala kwa odwala omwe ali ndi cerebellar ataxia (obadwa, obadwa, osakhala, komanso osadziwika). Zomwe anapezazi zikusonyeza kuti kuthandizira kungawonedwe kokha m'mayesero okhudzana ndi odwala omwe ali ndi cerebellar ataxia yobadwa ndi njira zomwe zimayendera. Kuphatikiza apo, chifukwa NALL imachepetsa neuroinflammation, yomwe ingayambitse kuvulala koopsa kwa ubongo, mayesero a NALL pofuna kuchiza kuvulala koopsa kwa ubongo angaganizidwe.