Nucleocytoplasmic Transport Defects: Cause or Consequence in Neurodegeneration and Aging?

Abstract

Nucleus is the most important organelle of a cell playing a critical role in the regulation of gene expression. The nuclear pore complexes (NPCs) spanning the NE are the largest protein complexes, having more than 30 different proteins called as nucleoporins (Nups). These structures play a key role in controlling bidirectional transport of RNA and specific proteins which carry nuclear import or export signals. Especially in long-lived cells, like neurons, protection of the nucleocytoplasmic transport machinery from accumulating external and internal insults has a special importance for maintaining genomic integrity and DNA repairement mechanisms. Recent studies suggest that structural and functional alterations in the NE and components of the NPC might lead to nucleocytoplasmic transport defects in both physiological aging and neurodegenerative disorders, in particular characterized by toxic protein aggregates. However, whether impaired nucleocytoplasmic transport is a cause or a consequence of such conditions is still unclear. In this review, it was aimed to summarize the molecular mechanisms underlying the nucleocytoplasmic transport defects. This information will not only provide insights to shared pathways in physiological and pathological conditions, but also open the way of thinking to develop novel therapeutic and/or protective approaches in the future.

Keywords

• Nucleocytoplasmic transport; Nuclear pore complex; Neurodegeneration;Aging.

Nucleocytoplasmic Transport Defects: Cause or Consequence in Neurodegeneration and Aging?

Öz

Çekirdek, hücrenin gen ekspresyonunun düzenlenmesinde kritik rol oynayan çok önemli bir organeldir. Nükleer zar içerisinde gömülü bulunan nükleer por kompleksleri (NPK) hücredeki en büyük protein kompleksleridir ve nükleoporin (Nups) olarak adlandırılan 30'dan fazla farklı proteine sahiptir. Bu yapılar, RNA'nın ve nükleer import veya export sinyalleri taşıyan spesifik proteinlerin çift yönlü olarak taşınımının kontrolünde önemli rol oynarlar. Özellikle de nöronlar gibi uzun ömürlü hücrelerde, genomik bütünlüğünün korunması ve DNA onarım mekanizmalarının işlevlerinin yerine getirebilmesi için nükleositoplazmik transport işletiminin giderek biriken iç ve dış hasarlardan korunması özel bir öneme sahiptir. Son çalışmalar, nükleer zardaki ve NPK bileşenlerindeki değişikliklerin hem fizyolojik yaşlanma hem de toksik protein agregatları ile karakterize olan nörodejeneratif hastalıklarda nükleositoplazmik transport bozukluklarına yol açabileceğine işaret etmektedir. Bununla birlikte, bozulmuş nükleositoplazmik taşınımın bu problemlerin nedeni mi yoksa sonucu mu olduğu konusu hala belirsizliğini korumaktadır. Bu derlemede, nükleositoplazmik transport kusurlarının altında yatan moleküler mekanizmaların özetlenmesi amaçlanmıştır. Bu bilgiler, fizyolojik ve patolojik durumlarda gözlenen ortak mekanizmalara ilişkin öngörü sağlamakla kalmayıp, aynı zamanda gelecekte yeni tedavi edici ve/veya koruyucu yaklaşımlar geliştirilmesi için düşünce yolunu da açacaktır.

Anahtar Kelimeler

• Nükleositoplazmik transport
• Nükleer por kompleksi
• Nörodejenerasyon
• Yaşlanma

Kaynakça

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