Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
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Index Copernicus  – 161.11; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2006, vol. 15, nr 3, May-June, p. 513–520

Publication type: review article

Language: Polish

Rola lipidów w patogenezie amyloidoz i w mechanizmach destrukcji komórki

The Role of Lipids in the Pathogenesis of Amyloidoses and in the Cell Destruction Mechanisms

Grzegorz Terlecki1,

1 Katedra i Zakład Biochemii Lekarskiej AM we Wrocławiu

Streszczenie

Choroba Alzheimera, Parkinsona i wiele innych to amyloidozy, związane z zaburzeniami spowodowanymi tworzeniem złogów w różnych tkankach przez swoiste białka, które u zdrowych osób nie wykazują takiej tendencji. Bezpośrednią przyczyną tych zaburzeń jest zmiana typowej dla tych białek konformacji na inną, sprzyjającą tworzeniu się z ich cząsteczek polimerycznych struktur, zwanych amyloidem. Za prawdopodobną przyczynę takiego zachowania się białek amyloidogennych uważa się ich wzajemne oddziaływanie z lipidami błon komórkowych, a szczególnie z fosfolipidami kwaśnymi. W niniejszej pracy, na przykładzie peptydu Aβ i białka α−synukleiny, budulca amyloidu, odpowiednio w chorobie Alzheimera i Parkinsona, przedstawiono mechanizm interakcji tych peptydów/białek z błoną lipidową. Opisano także powiązanie tej interakcji z budową oddziałującego peptydu i czynnikami utleniającymi, co ma kluczowe znaczenie dla polimeryzacji peptydu/białka. Innym, niepatologicznym skutkiem zmian konformacyjnych białka z udziałem lipidu/lipidów jest powstawanie aktywnych antynowotworowo konformerów takich białek, jak α−laktoalbumina czy histon H1. Są one zdolne do rozpoznawania komórek nowotworowych i niszczenia ich przez indukowanie apoptozy. W myśl najnowszej koncepcji genezy amyloidoz i innych procesów, u podstaw których leżą zmiany konformacyjne białek, kluczowym elementem jest błona komórkowa, a szczególnie fosfolipidy kwaśne wchodzące w skład jej dwuwarstwy lipidowej. Dzięki swoim właściwościom fizykochemicznym generują one przy powierzchni błony strefę o silnie obniżonym pH, która powoduje zmianę konformacji białek wchodzących w interakcję z błoną.

Abstract

Alzheimer’s disease, Parkinsons’s disease and many other disorders have been shown to be amyloidoses. They are dysfunctions caused by deposits of proteins, appearing in different tissues and formed by proteins which in the healthy organism do not have such a tendency. Changes in the conformation of the proteins lead to the conversion of the typical for them conformation into the other one causing the polymerization of the proteins into amyloid structures. The presented review shows that the amyloidogenic behaviour of proteins is generated probably by their interaction with cell membrane lipids and particularly with acidic phospholipids. Using Aβ−peptyde and the protein α−synuclein as representatives of amyloid forming elements in Alzheimer’s disease and Parkinson’s disease respectively, the mechanism of the interaction of the peptyde/protein with lipid membrane was shown. Relations between the interaction, the peptyde structure and oxidizing agents were also presented in the light of evidences indicating the key role of the interaction in the peptyde/protein molecules polymerization. The other, not pathological effect of protein conformation changes with lipid/lipids participation is the convertion of α−lactalbumin and histone H1 into conformers with antitumor activity, able to induce apoptosis in tumor cells. The principal idea of the newest conception of amyloidogenesis and other processes basically connected with changes of proteins conformation is that the cell membrane acidic phospholipids can provide the low−pH environment on the membrane, generating the convertion of the interacting protein conformation.

Słowa kluczowe

choroby konformacyjne, amyloidozy, lipidy, fosfolipidy kwaśne, ludzka α−laktoalbumina HAMLET zdolna do uśmiercania komórek nowotworowych

Key words

conformational diseases, amyloidoses, lipids, acidic phospholipids, human alpha−lactalbumin made lethal to tumor cells HAMLET

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