The role of the Amyloid Precursor Protein mutations and PERKdependent signaling pathways in the pathogenesis of Alzheimer’s disease

Wioletta Rozpędek; Alicja Nowak; Dariusz Pytel; Dawid Lewko; J. Alan Diehl; Ireneusz Majsterek

doi:10.1515/fobio-2016-0005

Autor

Wioletta Rozpędek Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
Alicja Nowak Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
Dariusz Pytel Medical University of South Carolina, Hollings Cancer Center, Department of Biochemistry and Molecular Biology
Dawid Lewko Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry
J. Alan Diehl Medical University of South Carolina, Hollings Cancer Center, Department of Biochemistry and Molecular Biology
Ireneusz Majsterek Medical University of Lodz, Military-Medical Faculty, Department of Clinical Chemistry and Biochemistry

DOI:

https://doi.org/10.1515/fobio-2016-0005

Słowa kluczowe:

Amyloid β, Endoplasmic Reticulum stress, Unfolded Protein Response, eIF2α, CHOP

Abstrakt

Choroba Alzheimera (ang. Alzheimer’s disease, AD) jest przewlekłą, najczęściej występującą, chorobą neurodegeneracyjną prowadzącą do nieodwracalnych zmian w strukturze, biochemii i funkcjach mózgu. Neurodegeneracja Ośrodkowego Układu Nerwowego (OUN) jest wynikiem odkładania toksycznych złogów amyloidu β (Aβ) w tkance nerwowej mózgu. Rozwój AD jest przyczyną skomplikowanych interakcji między podłożem genetycznym, a czynnikami biologicznymi, które aktywują złożone szlaki molekularne w przebiegu schorzenia. Za jedną z głównych przyczyn uważa się mutacje występujące w genie kodującym Prekursorowe białko amyloidu β (ang. Amyloid beta Precursor Protein, APP) zlokalizowane w pobliżu cięcia białka APP przez wysoce specyficzne sekretazy: α, β oraz γ. Generowanie toksycznej formy Aβ o długości 42-óch aminokwasów, odkładanego w tkance mózgowej jako płytki starcze, zachodzi poprzez drogę amyloidogenną, w której uczestniczą sekretazy β oraz γ. Na podłożu molekularnym główną przyczyną rozwoju choroby AD jest akumulacja błędnie sfałdowanych lub niesfałdowanych białek w lumen Retikulum Plazmatycznego (ang. Endoplasmic Reticulum, ER). Skutkuje to bezpośrednim wywołaniem stresu ER, który prowadzi do aktywacji kinazy PERK, a następnie fosforylacji eukariotycznego czynnika inicjacji translacji 2 (eIF2α). W rezultacie w komórce nerwowej inhibowana jest translacja większości białek oraz dochodzi do preferencyjnej translacji wyłącznie takich białek takich jak ATF4 (ang. Activating Transcriptor 4) oraz, wyniku długotrwałych warunków stresowych, CHOP (ang. CCAAT-enhancer-binding protein homologous protein). Nadekspresja białka CHOP prowadzi do wzmocnienia ekspresji genów kodujących: pro-apoptotyczne białka BH3 domain-only, GADD34 (ang. DNA damage-inducible protein, GADD34 oraz białko o aktywności oksydoreduktazy ER (ang. ER oxidoreductin 1α, ERO1α). W warunkach wysokiego stężenia białka CHOP zostaje osłabiona ekspresja genów kodujących anty-apoptotyczne białka Bcl-2. W rezultacie masa tkanki nerwowej mózgu ulega znaczącemu obniżeniu w wyniku postępującego procesu neurodegeneracji na drodze apoptotycznej śmierć komórkowej w przebiegu AD.

Pobrania

Brak dostępnych danych do wyświetlenia.

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