LAMP2-Centered Autophagy Network and HDAC Inhibitors as Therapeutic Leads in Alzheimer’s and Parkinson’s Diseases: A Bioinformatic Analysis

Abstract

Alzheimer hastalığı (AD) ve Parkinson hastalığı (PD) en yaygın iki nörodejeneratif hastalıktır ve her ikisi de belirgin proteinopatiler ve ilerleyici nöronal kayıpla kendisini göstermektedirler. Yapılan çalışmalar her iki hastalıkta da birleşen bir mekanizma olarak otofaji disfonksiyonuna işaret edilmektedir. Bu nedenle çalışmamızdaki temel amaç biyoinformatik teknikler kullanarak AD ve PD'de otofaji ve apoptozla ilişkili ortak upregüle olan genleri belirlemek ve bu genleri hedef alan yeni tedavi bileşenlerini ortaya çıkarmaktır. Çalışmamızda kamuya açık transkriptomik verileri (AD için GSE5281, GSE48350; PD için GSE49036) kullanarak, farklı şekilde ifade edilen genler (DEG'ler) belirlenmiştir ve bunları İnsan Otofaji Veritabanı'ndan derlenen otofaji ve apoptozla ilişkili genlerle sınırlandırılmıştır. Sonuçlarımıza göre CARD8, FXN, LAMP2, EVI2B, MYOT, P2RX7 ve MEGF10 genleri her iki durumda da sürekli olarak upregüle edilirken, ELAPOR1 downregüle edilmiştir. PPI ağ analizi sonuçlarımız LAMP2'nin lizozomal otofajik füzyonu düzenleyen merkezi bir molekül olduğunu vurgulamaktadır. Gen zenginleştirme analizleri, otofaji, lizozomal aktivite ve inflamasyonda rol oynayan yolakları işaret etmektedir. Enrichr platformunda yer alan DSigDB veritabanı kullanılarak yapılan ilaç yeniden kullanım analizi, histon deasetilaz (HDAC) inhibitörleri olan Vorinostat (suberoylanilid hidroksamik asit, SAHA), Trikostatin A (TSA) ve Valproik Asit’in (VPA) bu ortak gen ağını düzenleyebilecek umut verici ajanlar olarak öne çıktığını göstermiştir. Bu bulgular, AD ve PD'nin ortak patolojik özelliklerini ele alma potansiyeline sahip bir dizi otofaji ve apoptozla ilişkili hedef ve tedavi sunmaktadır.

Keywords

• Alzheimer Hastalığı
• Parkinson Hastalığı
• Otofaji
• Apoptozis
• İlaç Yeniden Kullanımı
• HDAC İnhibitörleri
• Transkriptomik

LAMP2-Centered Autophagy Network and HDAC Inhibitors as Therapeutic Leads in Alzheimer’s and Parkinson’s Diseases: A Bioinformatic Analysis

Abstract

Among neurodegenerative disorders, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most commonly diagnosed, and both present with distinct proteinopathies and progressive neuronal loss. Studies have implicated autophagy dysfunction as a common mechanism in both diseases. Therefore, the primary objective of our study is to use bioinformatics techniques to identify commonly upregulated genes associated with autophagy and apoptosis in AD and PD and to develop novel therapeutic agents targeting these genes. Using publicly available transcriptomic data (GSE5281 and GSE48350 for AD; GSE49036 for PD), differentially expressed genes (DEGs) are identified and restricted to autophagy and apoptosis related genes compiled from the Human Autophagy Database. According to our results, the genes CARD8, FXN, LAMP2, EVI2B, MYOT, P2RX7, and MEGF10 are consistently upregulated in both conditions, while ELAPOR1 is downregulated. Our PPI network analysis results highlight LAMP2 as a central molecule regulating lysosomal-autophagic fusion. Gene enrichment analyses implicate pathways involved in autophagy, lysosomal activity, and inflammation. Drug repurposing analysis using the DSigDB database on the Enrichr platform has shown that the histone deacetylase (HDAC) inhibitors Vorinostat (suberoylanilide hydroxamic acid, SAHA), Trichostatin A (TSA), and Valproic Acid (VPA) stand out as promising agents that may regulate this common gene network. These findings provide a number of autophagy- and apoptosis-related targets and therapies with the potential to address shared pathological features of AD and PD.

Keywords

• Alzheimer’s Disease
• Parkinson’s Disease
• Autophagy
• Apoptosis
• Drug Repurposing
• HDAC Inhibitors
• Transcriptomics

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