Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders

Abstract

Liquid–liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.

Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes

“…Among the hub genes derived from the up-regulated DEGs, no ALS-related literature was found for the EEF1A1 , RPLP0 , EEF2 , CCT2 , RPL12 and RPL15 genes. However, studies related to ALS were identified for the EIF4A1 [ 44 ], HNRNPR [ 45 ], HNRNPA1 [ 45 , 46 ] and PABPC1 genes [ 47 ]. In the case of hub genes obtained from the down-regulated DEGs, only the NDUFA4 gene was associated with ALS-related studies [ 48 ].…”

“…Elevated expression of HNRNPR and HNRNPA1 together with a subset of human RNA-binding proteins that bind to the GGGGCC repeat RNA of the C9orf72 gene, one of the most common causes of ALS, reduces the level of GGGGCC repeat RNA, leading to the suppression of neurodegeneration. In addition, the involvement of HNRNPA1 in the different molecular pathways related to ALS neurodegeneration is increasingly being studied, as this protein is thought to play a key role in mRNA transcription, splicing, stability, transport and translation [ 46 , 63 ]. The PABPC1 gene has been associated with the UBQLN2 gene, one of the key genes linked to amyotrophic lateral sclerosis (ALS).…”

SERBP1 interacts with PARP1 and is present in PARylation-dependent protein complexes regulating splicing, cell division, and ribosome biogenesis

“…This result suggests that PARP1 modulates liquid-liquid phase separation (LLPS) and a PARylation-mediated mechanism is likely involved in SERBP1’s pathological transition from condensate to aggregate. Several RBPs containing intrinsically disordered regions, like SERBP1, have been shown to display alterations in LLPS in neurodegenerative diseases (112, 113)…”

Initiation of hnRNPA1 Low-Complexity Domain Condensation Monitored by Dynamic Light Scattering

“…Protein condensation is a process by which proteins partition into a protein-rich phase, distinct from the more dilute bulk phase. The field of protein condensation has gained extraordinary popularity within the recent decade, with particular interest in biomolecular condensates (BMCs): cellular protein condensates with functional roles in spatiotemporal organization and regulation of biological processes [1][2][3], as well as involvement in diseases, such as neurodegeneration and cancer [2,[4][5][6].…”

“…There is evidence 2 of 9 that these solid pathologic condensates originate from liquid condensates. Under stressful or pathological conditions, liquid condensates can undergo a liquid-to-solid phase transition, resulting in protein fibrillation [4,9].…”