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Kunyange zvazvo zvisingawanzoitiki, chiitiko chese chekuchengetedza lysosomal chinenge 1 mu 5,000 yekuzvarwa kwehupenyu. Pamusoro pezvo, pane angangoita makumi manomwe anozivikanwa lysosomal kuchengetedza kusagadzikana, 70% inokanganisa iyo yepakati tsinga system. Aya ma-gene-gene kusagadzikana anokonzera kusagadzikana kwe lysosomal, zvichikonzera kusagadzikana kwemetabolism, dysregulation yemammalian target protein yerapamycin (mTOR, iyo inowanzodzivisa kuzvimba), kukanganisa autophagy, uye nerve cell death. Mishonga yakati wandei inonangana neiyo pathologic nzira dzeiyo lysosomal kuchengetedza chirwere yakabvumidzwa kana iri pasi pekuvandudzwa, kusanganisira enzyme replacement therapy, substrate reduction therapy, molecular chaperone therapy, gene therapy, gene editing, uye neuroprotective therapy.

Niemann-pick chirwere cherudzi C is lysosomal storage cellular cholesterol transport disorder inokonzerwa nebiallelic mutations muNPC1 (95%) kana NPC2 (5%). Zviratidzo zverudzi rweC rwechirwere cheNiemann-Pick zvinosanganisira kukurumidza, kunouraya kuderera kwetsinga muhucheche, nepo mafomu ekutanga epwere, pwere, uye akura anosanganisira splenomegaly, supranuclear gaze paralysis uye cerebellar ataxia, dysarticulationia, uye dementia inofambira mberi.

Muchinyorwa ichi chejenari, Bremova-Ertl et al vanorondedzera mhedzisiro yekaviri-mapofu, placebo-inodzorwa, crossover kuyedza. Muedzo wakashandisa mukana weurouroprotective agent, iyo amino acid analogue N-acetyl-L-leucine (NALL), kurapa Niemann-Pick chirwere cherudzi C. Vakatora 60 zviratidzo zvevechiri kuyaruka uye varwere vakuru uye zvigumisiro zvakaratidza kuwedzera kukuru kwehuwandu hwehuwandu (primary endpoint) yeAtaxia Assessment uye Rating Scale.

Miedzo yekiriniki yeN-acetyl-DL-leucine (Tanganil), nhangemutange yeNALL uye n-acetyl-D-leucine, inoita seinofambiswa zvakanyanya neruzivo: maitiro echiito haana kunyatsojekeswa. N-acetyl-dl-leucine yakabvumidzwa kurapwa kweacute vertigo kubvira kuma1950; Mhuka dzemhando dzinoratidza kuti mushonga unoshanda nekuenzanisazve overpolarization uye depolarization ye medial vestibular neurons. Zvadaro, Strupp et al. yakashuma migumisiro yekudzidza kwenguva pfupi umo vakaona kuvandudzwa kwezviratidzo muvarwere ve13 vane degenerative cerebellar ataxia yezvakasiyana-siyana etiologies, zvakawanikwa zvakadzora kufarira kutarisa mushonga zvakare.

Iyo nzira iyo n-acetyl-DL-leucine inovandudza tsinga inoshanda haisati yanyatsojeka, asi zvakawanikwa mumhando mbiri dzembeva, imwe yeNiemann-Pick chirwere cherudzi C uye imwe yeGM2 ganglioside storage disorder Variant O (Sandhoff disease), imwe neurodegenerative lysosomal disease, yakaita kuti pfungwa dziende kuNALL. Kunyanya, kupona kweNpc1-/- mbeva dzakabatwa nen-acetyl-DL-leucine kana NALL (L-enantiomers) kwakavandudzwa, nepo kurarama kwemakonzo akabatwa nen-acetyl-D-leucine (D-enantiomers) hakuna, zvichiratidza kuti NALL ndiyo inoshanda fomu yemushonga. Muchidzidzo chakafanana cheGM2 ganglioside storage disorder variant O (Hexb-/-), n-acetyl-DL-leucine yakaguma nekuwedzera zvine mwero asi kwakakosha kwehupenyu mumakonzo.

Kuti uongorore maitiro ekuita kwen-acetyl-DL-leucine, vatsvakurudzi vakatsvaga nzira ye metabolic ye leucine nekuyera metabolites mu cerebellar tissues yemhuka dzinoshanduka. Mune akasiyana O modhi yeGM2 ganglioside kuchengetedza kusagadzikana, n-acetyl-DL-leucine inojairisa glucose uye glutamate metabolism, inowedzera autophagy, uye inowedzera mazinga e superoxide dismutase (inoshingaira oxygen scavger). Mumuenzaniso weC wechirwere cheNiemann-Pick, kuchinja kweglucose uye antioxidant metabolism uye kuvandudzwa kwemitochondrial simba metabolism yakaonekwa. Kunyangwe L-leucine ine simba mTOR activator, pakanga pasina shanduko padanho kana phosphorylation yemTOR mushure mekurapwa nen-acetyl-DL-leucine kana enantiomers ayo mune chero mbeva modhi.

Iyo neuroprotective mhedzisiro yeNALL yakaonekwa mune mbeva modhi yekortical impingement yakakonzera kukuvara kwehuropi. Izvi zvinosanganisira kudzikisa neuroinflammatory mamaki, kuderedza cortical cell kufa, uye kugadzirisa autophagy flux. Mushure mekurapa kweNALL, iyo mota uye yekuziva mabasa emakonzo akakuvadzwa akadzoserwa uye saizi yeronda yakaderedzwa.

Mhinduro yekuzvimba yepakati tsinga system ndiyo chiratidzo cheakawanda neurodegenerative lysosomal kuchengetedza kusagadzikana. Kana neuroinflammation inogona kuderedzwa neNALL kurapwa, zviratidzo zvekiriniki zvevakawanda, kana zvisiri zvese, neurodegenerative lysosomal kuchengetedza kusagadzikana kunogona kuvandudzwa. Sezvinoratidzwa neongororo iyi, NALL inotarisirwawo kuve nekudyidzana nemamwe marapirwo echirwere chelysosomal storage.

Mazhinji lysosomal kuchengetedza matambudziko anobatanidzwawo necerebellar ataxia. Maererano nekuongorora kwenyika dzakawanda kunosanganisira vana nevakuru vane GM2 ganglioside storage disorders (Tay-Sachs chirwere uye Sandhoff chirwere), ataxia yakaderedzwa uye kurongeka kwakanaka kwemotokari kwakavandudzwa mushure mekurapa kweNALL. Zvisinei, muedzo wakakura, wakawanda, wakapetwa kaviri-mapofu, wakarongeka, wakagadziriswa wakaratidza kuti n-acetyl-DL-leucine yakanga isingashandisi kliniki kune varwere vakasanganiswa (vakagarwa nhaka, vasina nhaka, uye vasina kutsanangurwa) cerebellar ataxia. Kuwana uku kunoratidza kuti kushanda kunogona kungoonekwa mumiedzo inosanganisira varwere vane nhaka yecerebellar ataxia uye nzira dzakabatana dzekuita dzakaongororwa. Mukuwedzera, nokuti NALL inoderedza neuroinflammation, iyo inogona kutungamirira mukukuvadzwa kwehuropi, miedzo yeNALL yekurapa kwekukuvara kwehuropi inogona kufungwa.