labarai

Ko da yake ba kasafai ba ne, gabaɗayan abin da ke faruwa na ajiyar lysosomal ya kai kusan 1 a cikin kowace haihuwar 5,000 masu rai. Bugu da ƙari, daga cikin kusan 70 da aka sani da rikice-rikice na lysosomal ajiya, 70% yana shafar tsarin kulawa na tsakiya. Wadannan cututtukan guda ɗaya suna haifar da rashin aiki na lysosomal, wanda ke haifar da rashin zaman lafiya na rayuwa, dysregulation na furotin na rapamycin na mammalian (mTOR, wanda yakan hana kumburi), rashin lafiyar autophagy, da kuma mutuwar kwayoyin halitta. An yarda da wasu hanyoyin kwantar da hankali waɗanda ke yin niyya kan hanyoyin cututtukan cututtukan cututtukan cututtukan lysosomal ko kuma suna ƙarƙashin haɓakawa, gami da maye gurbin enzyme, jiyya na rage juzu'i, maganin chaperone na ƙwayoyin cuta, jiyya na ƙwayoyin cuta, gyaran kwayoyin halitta, da kuma neuroprotective far.

Niemann-pick cuta nau'in C cuta ce ta lysosomal ajiyar ƙwayar cuta ta ƙwayar cuta wacce ta haifar da maye gurbi a cikin ko dai NPC1 (95%) ko NPC2 (5%). Alamun nau'in C na cututtukan Niemann-Pick sun haɗa da sauri, raguwar ƙwayar ƙwayar cuta a cikin jariri, yayin da ƙananan yara, matasa, da kuma manya na farko sun hada da splenomegaly, supranuclear gaze paralysis da cerebellar ataxia, dysarticleia, da ciwon ci gaba.

A cikin wannan fitowar ta mujallolin, Bremova-Ertl et al sun ba da rahoton sakamakon gwajin makafi biyu, mai sarrafa wuribo, gwaji na crossover. Gwajin ya yi amfani da wakili mai yuwuwar neuroprotective, amino acid analogue N-acetyl-L-leucine (NALL), don magance nau'in cutar Niemann-Pick C. Sun dauki nauyin 60 masu nuna alamun bayyanar cututtuka da marasa lafiya na manya kuma sakamakon ya nuna babban ci gaba a cikin jimlar ci gaba (madaidaicin matsayi) na Ataxia Assessment and Rating Scale.

Gwajin gwaji na asibiti na N-acetyl-DL-leucine (Tanganil), tseren tseren NALL da n-acetyl-D-leucine, da alama sun fi kwarewa ta hanyar kwarewa: tsarin aikin ba a bayyana a fili ba. An amince da N-acetyl-dl-leucine don maganin m vertigo tun daga 1950s; Samfurori na dabba suna ba da shawarar cewa miyagun ƙwayoyi suna aiki ta hanyar daidaitawa da haɓakawa da ƙaddamar da ƙananan ƙwayoyin cuta na tsakiya na vestibular. Bayan haka, Strup et al. ya ba da rahoton sakamakon binciken na ɗan gajeren lokaci wanda suka lura da ci gaba a cikin alamun bayyanar cututtuka a cikin marasa lafiya 13 tare da degenerative cerebellar ataxia na nau'i-nau'i daban-daban, binciken da ya sake haifar da sha'awar sake kallon miyagun ƙwayoyi.

Hanyar da n-acetyl-DL-leucine ke inganta aikin jijiya bai riga ya bayyana ba, amma binciken da aka samu a cikin nau'ikan linzamin kwamfuta guda biyu, daya daga cikin nau'in cutar Niemann-Pick C da ɗayan GM2 ganglioside storage disorder Variant O (Cutar Sandhoff), wani cututtukan lysosomal neurodegenerative, sun sa hankali ya juya zuwa NALL. Musamman, rayuwa na Npc1-/- berayen da aka bi da su tare da n-acetyl-DL-leucine ko NALL (L-enantiomers) sun inganta, yayin da rayuwar berayen da aka yi amfani da su tare da n-acetyl-D-leucine (D-enantiomers) bai yi ba, yana nuna cewa NALL shine nau'i mai aiki na miyagun ƙwayoyi. A cikin irin wannan binciken na GM2 ganglioside storage disorder bambance-bambancen O (Hexb-/-), n-acetyl-DL-leucine ya haifar da matsakaicin matsakaici amma gagarumin tsawo na rayuwa a cikin mice.

Don bincika tsarin aikin n-acetyl-DL-leucine, masu binciken sun binciki hanyar rayuwa ta leucine ta hanyar auna metabolites a cikin kyallen jikin cerebellar na dabbobin mutant. A cikin bambance-bambancen O model na GM2 ganglioside ajiya cuta, n-acetyl-DL-leucine normalizes glucose da glutamate metabolism, ƙara autophagy, da kuma ƙara matakan superoxide dismutase (wani aiki oxygen scavger). A cikin samfurin C na cutar Niemann-Pick, an lura da canje-canje a cikin glucose da antioxidant metabolism da ingantawa a cikin makamashi na mitochondrial. Kodayake L-leucine shine mai kunnawa mTOR mai ƙarfi, babu wani canji a matakin ko phosphorylation na mTOR bayan jiyya tare da n-acetyl-DL-leucine ko masu haɓakawa a cikin kowane ƙirar linzamin kwamfuta.

An lura da tasirin neuroprotective na NALL a cikin ƙirar linzamin kwamfuta na ƙwanƙwasa ƙwanƙwasa wanda ya haifar da raunin kwakwalwa. Wadannan tasirin sun haɗa da rage alamun neuroinflammatory, rage mutuwar kwayar cutar cortical, da inganta haɓakar autophagy. Bayan jiyya na NALL, an dawo da aikin motar da fahimi na ɓerayen da suka ji rauni kuma an rage girman raunin.

Amsa mai kumburi na tsarin juyayi na tsakiya shine alamar mafi yawan cututtukan cututtuka na lysosomal neurodegenerative. Idan neuroinflammation za a iya rage tare da NALL magani, da asibiti bayyanar cututtuka da yawa, idan ba duka, neurodegenerative lysosomal ajiya cuta iya inganta. Kamar yadda wannan binciken ya nuna, ana kuma sa ran NALL ya sami haɗin gwiwa tare da wasu hanyoyin kwantar da hankali don cutar ajiyar lysosomal.

Yawancin rikice-rikice na ajiyar lysosomal kuma suna da alaƙa da cerebellar ataxia. Bisa ga binciken kasa da kasa da ya shafi yara da manya tare da GM2 ganglioside ajiya cuta (Cutar Tay-Sachs da cutar Sandhoff), an rage ataxia kuma an inganta ingantaccen tsarin motsa jiki bayan jiyya na NALL. Duk da haka, babban, multicenter, makafi biyu, bazuwar, gwajin gwaji na placebo ya nuna cewa n-acetyl-DL-leucine ba ta da tasiri a cikin marasa lafiya tare da gauraye (gado, wadanda ba a gado, da ba a bayyana ba) cerebellar ataxia. Wannan binciken yana nuna cewa ana iya lura da inganci kawai a cikin gwaje-gwajen da suka shafi marasa lafiya tare da ataxia na cerebellar da aka gada da kuma hanyoyin da aka haɗa da yin nazari. Bugu da ƙari, saboda NALL yana rage ƙwayar neuroinflammation, wanda zai iya haifar da raunin kwakwalwa mai rauni, ana iya la'akari da gwaji na NALL don maganin raunin kwakwalwa.