Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

Abstract

RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid–liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases.

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

“…The discovery that NIRs counter deleterious phase transitions of RBPs has led to the idea that NIRs can be utilized for therapeutic applications to restore RBP homeostasis and mitigate neurodegeneration [ 14 , 15 , 17 , 18 , 42 , 142 ]. It is unclear why TNPO1 accumulates in FUS-positive inclusions in FTLD-FUS rather than preventing FUS aggregation, since TNPO1 can efficiently reduce phase separation of hypomethylated FUS in vitro and in cells [ 40 , 49 ].…”

Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

“…, TDP-43). For example, the study from Girdhar and colleagues identified an acridine derivative, that is, AIM4, as an anti-TDP-43 aggregation molecule that binds to TDP-43 disordered region ( 154 , 156 ). A third way is the use of drugs that target mediators influencing LLPS such as post-translational modifications of proteins or the epigenetic state of DNA and RNA, which are both essential for the nucleation of condensates ( 157 , 158 ).…”

Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

“…Due to their biomolecular properties, R-DPRs have been demonstrated to undergo LLPS [reviewed elsewhere (Mann and Donnelly, 2021 ; Solomon et al, 2021 ; Yoshizawa and Guo, 2021 ; Girdhar and Guo, 2022 )], a process in which proteins demix from aqueous solutions into liquid-like droplets (also referred to as condensates), which under abnormal conditions can mature into less dynamic fibrillar/aggregate-like structures, potentially underlying protein aggregation in neurodegenerative diseases. LLPS (also referred to interchangeably as condensation) is a fundamental property of many proteins containing disordered domains (such as FG-Nups) and RNA binding proteins (such as TDP-43, FUS, and stress granule protein G3BP1), and is crucial for many biological processes.…”