litaba

Le hoja e batla e sa tloaeleha, ketsahalo e akaretsang ea lysosomal storage e ka ba 1 ho bana ba bang le ba bang ba 5,000 ba hlahang. Ho feta moo, ho mafu a ka bang 70 a tsebahalang a ho boloka lysosomal, 70% a ama tsamaiso ea methapo e bohareng. Mathata ana a lefutso le le leng a baka ho se sebetse ha lysosomal, ho fella ka ho se tsitse ha metabolism, ho senyeha ha protheine e lebisitsoeng ho mammalian ea rapamycin (mTOR, eo ka tloaelo e thibelang ho ruruha), ho senyeha ha autophagy, le lefu la lisele tsa methapo. Liphekolo tse 'maloa tse shebaneng le mekhoa ea motheo ea lefu la lysosomal li amohetsoe kapa li ntse li tsoela pele ho ntlafatsoa, ​​​​ho kenyeletsoa kalafo ea phetoho ea enzyme, kalafo ea phokotso ea karoloana, kalafo ea molecular chaperone, gene therapy, gene editing le neuroprotective therapy.

Mofuta oa lefu la Niemann-pick C ke lysosomal storage cellular cholesterol transport disorder e bakoang ke liphetoho tsa biallelic ho NPC1 (95%) kapa NPC2 (5%). Matšoao a mofuta oa C oa lefu la Niemann-Pick a kenyelletsa ho theoha ka potlako, ho bolaeang ha methapo ea kutlo boseeng, ha mefuta ea ho qala ha bacha, bacha le batho ba baholo e kenyelletsa splenomegaly, supranuclear gaze paralysis le cerebellar ataxia, dysarticulationia, le dementia e tsoelang pele.

Khatisong ena ea koranta, Bremova-Ertl et al ba tlaleha liphetho tsa teko e habeli e foufetseng, e laoloang ke placebo, crossover. Teko e ile ea sebelisa e ka 'nang ea e-ba moemeli oa neuroprotective, amino acid analogue N-acetyl-L-leucine (NALL), ho phekola mofuta oa lefu la Niemann-Pick C. Ba ile ba hira bakuli ba nang le matšoao a 60 a lilemong tsa bocha le batho ba baholo 'me liphello li bontšitse ntlafatso e kholo ho palo eohle (mafelo a mantlha) a Ataxia Assessment le Rating Scale.

Liteko tsa kliniki tsa N-acetyl-DL-leucine (Tanganil), morabe oa NALL le n-acetyl-D-leucine, li bonahala li khannoa haholo ke boiphihlelo: mokhoa oa ts'ebetso ha o so hlakisoe ka ho hlaka. N-acetyl-dl-leucine e amohetsoe bakeng sa kalafo ea lefu la vertigo ho tloha lilemong tsa bo-1950; Mefuta ea liphoofolo e fana ka maikutlo a hore sethethefatsi se sebetsa ka ho leka-lekanya ho fetella le ho senyeha ha methapo ea methapo ea methapo ea methapo. Ka mor'a moo, Strupp et al. e tlalehile liphello tsa thuto ea nako e khutšoanyane eo ho eona ba ileng ba bona ntlafatso ea matšoao ho bakuli ba 13 ba nang le cerebellar ataxia e fokolang ea li-etiologies tse sa tšoaneng, liphuputso tse ileng tsa tsosolosa thahasello ea ho sheba lithethefatsi hape.

Mokhoa oo ka oona n-acetyl-DL-leucine e ntlafatsang ts'ebetso ea methapo ha e e-s'o hlake, empa liphuputso tsa mefuta e 'meli ea litoeba, e' ngoe ea mofuta oa lefu la Niemann-Pick C le e 'ngoe ea GM2 ganglioside storage disorder Variant O (lefu la Sandhoff), lefu le leng la neurodegenerative lysosomal, le susumelitse tlhokomelo ho retelehela ho NALL. Ka ho khetheha, ho pholoha ha litoeba tsa Npc1-/- tse tšoaroang ka n-acetyl-DL-leucine kapa NALL (L-enantiomers) ho ile ha ntlafala, ha ho pholoha ha litoeba tse tšoaroang ka n-acetyl-D-leucine (D-enantiomers) ha hoa ka ha fana ka maikutlo a hore NALL ke mofuta o sebetsang oa lithethefatsi. Phuputsong e tšoanang ea GM2 ganglioside storage disorder variant O (Hexb-/-), n-acetyl-DL-leucine e hlahisitse katoloso e itekanetseng empa e le ea bohlokoa ea nako ea bophelo ho litoeba.

Ho hlahloba mokhoa oa ts'ebetso oa n-acetyl-DL-leucine, bafuputsi ba ile ba batlisisa tsela ea metabolic ea leucine ka ho lekanya metabolite meleng ea cerebellar ea liphoofolo tse fetohileng. Ka mofuta o fapaneng oa O oa GM2 ganglioside storage disorder, n-acetyl-DL-leucine e tloaeleha metabolism ea glucose le glutamate, e eketsa autophagy, 'me e eketsa maemo a superoxide dismutase (e sebetsang ka oksijene scavger). Mohlaleng oa C oa lefu la Niemann-Pick, liphetoho tsa tsoekere le metabolism ea antioxidant le ntlafatso ea metabolism ea matla a mitochondrial li ile tsa bonoa. Le hoja L-leucine e le activator e matla ea mTOR, ha hoa ka ha e-ba le phetoho boemong kapa phosphorylation ea mTOR ka mor'a phekolo ea n-acetyl-DL-leucine kapa li-enantiomers tsa eona ho mofuta ofe kapa ofe oa mouse.

Phello ea methapo ea kutlo ea NALL e hlokometsoe ka mohlala oa mouse oa cortical impingement e bakiloeng ke kotsi ea boko. Litlamorao tsena li kenyelletsa ho theola matšoao a neuroinflammatory, ho fokotsa lefu la cortical cell, le ho ntlafatsa phallo ea autophagy. Ka mor'a phekolo ea NALL, mesebetsi ea motlakase le ea kelello ea litoeba tse lemetseng li ile tsa tsosolosoa 'me boholo ba leqeba bo fokotsehile.

Karabelo ea ho ruruha ea tsamaiso ea methapo e bohareng ke letšoao la mathata a mangata a neurodegenerative lysosomal storage. Haeba neuroinflammation e ka fokotsoa ka kalafo ea NALL, matšoao a kliniki a ba bangata, haeba e se kaofela, mathata a polokelo ea methapo ea methapo a ka ntlafatsoa. Joalokaha thuto ena e bontša, NALL e boetse e lebelletsoe ho ba le likamano le liphekolo tse ling bakeng sa lefu la polokelo ea lysosomal.

Mathata a mangata a ho boloka lysosomal a boetse a amahanngoa le cerebellar ataxia. Ho ea ka phuputso ea machaba e amang bana le batho ba baholo ba nang le bothata ba ho boloka li-ganglioside tsa GM2 (lefu la Tay-Sachs le lefu la Sandhoff), ataxia e ile ea fokotseha 'me tšebelisano e ntle ea motlakase ea ntlafala ka mor'a phekolo ea NALL. Leha ho le joalo, teko e kholo, e mengata, e nang le lifofu tse peli, e sa tloaelehang, e laoloang ke placebo e bontšitse hore n-acetyl-DL-leucine e ne e sa sebetse ka katleho ho bakuli ba nang le cerebellar ataxia e tsoakiloeng (e futsitsoeng, e sa futsitsoeng le e sa hlalosoang). Tlhahiso ena e fana ka maikutlo a hore katleho e ka bonoa feela litekong tse amang bakuli ba nang le lefutso la cerebellar ataxia le mekhoa e amanang le ts'ebetso e hlahlojoang. Ho phaella moo, hobane NALL e fokotsa neuroinflammation, e ka lebisang kotsi e bohloko ea boko, liteko tsa NALL bakeng sa phekolo ea kotsi e bohloko ea boko li ka nkoa.