Sự tăng cường biểu hiện của Parkin trong các tế bào tiền thân thần kinh từ bệnh nhân mắc bệnh Parkinson đã dịch chuyển transcriptome hướng tới trạng thái bình thường

Molecular Neurobiology - Tập 60 - Trang 3522-3533 - 2023
Olga Lebedeva1,2, Daniil Poberezhniy3,4, Ekaterina Novosadova3, Tatiana Gerasimova3, Lyudmila Novosadova3, Elena Arsenyeva3, Ekaterina Stepanenko3, Darya Shimchenko3, Egor Volovikov1, Ksenia Anufrieva1,2, Sergey Illarioshkin5, Maria Lagarkova1,2, Igor Grivennikov3, Vyacheslav Tarantul3, Valentina Nenasheva3
1Lopukhin Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical and Biological Agency of the Russian Federation, Moscow, Russia
2Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
3Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, Moscow, Russia
4Faculty of Biotechnology and Industrial Ecology, D.I. Mendeleyev University of Chemical Technology of Russia, Moscow, Russia
5Research Center of Neurology, Moscow, Russia

Tóm tắt

Bệnh Parkinson (PD) là một bệnh lý thoái hóa thần kinh do sự mất mát tiến triển của các nơron dopaminergic trong vùng chất đen. BPD vị thành niên được biết đến là có liên quan mạnh mẽ đến các đột biến trong gen PARK2 mã hóa ligase ubiquitin E3 Parkin. Mặc dù có nhiều nghiên cứu, các cơ chế phân tử kích thích PD vẫn chủ yếu chưa được biết đến. Tại đây, chúng tôi đã so sánh transcriptome của dòng tế bào tiền thân thần kinh (NP), được lấy từ một bệnh nhân PD có đột biến PARK2 dẫn đến mất Parkin, với transcriptome của cùng một dòng NP nhưng biểu hiện Parkin chuyển gen. Chúng tôi phát hiện rằng sự biểu hiện quá mức của Parkin dẫn đến sự phục hồi đáng kể của transcriptome của NP về trạng thái bình thường, cho thấy rằng sự thay đổi trong quá trình phiên mã ở NP lấy từ PD chủ yếu được gây ra bởi các đột biến PARK2. Trong số các gen bị rối loạn đáng kể trong NP lấy từ PD, 106 gen rõ ràng đã khôi phục biểu hiện của chúng sau khi khôi phục mức Parkin. Dựa trên các tập hợp gen đã chọn, chúng tôi đã phát hiện các con đường Gene Ontology (GO) được làm giàu bao gồm tín hiệu, vận chuyển và chuyển hóa chất truyền dẫn thần kinh, phản ứng với kích thích và quá trình apoptosis. Đáng chú ý, thụ thể dopamin D4 trước đây đã được liên kết với PD dường như liên quan đến số lượng tối đa các con đường GO giàu có và do đó có thể được coi là một yếu tố kích thích tiềm năng của sự tiến triển của PD. Những phát hiện của chúng tôi có thể giúp trong việc sàng lọc các mục tiêu tiềm năng để điều trị PD.

Từ khóa

#Bệnh Parkinson #Parkin #Gen PARK2 #Tế bào tiền thân thần kinh #Transcriptome #Đột biến #Tín hiệu tế bào #Chuyển hóa dopamine #Thụ thể dopamine D4.

Tài liệu tham khảo

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