Current Protein and Peptide Science - Volume 26, Issue 10, 2025

Neoplastic transformation of B cells of the post-germinative center can lead to oncohematological dyscrasias, which often results in an abnormal production of monoclonal immunoglobulin light chains. The non-physiological production of large amounts of IgG light chains leads to the formation of extracellular deposits called 'aggregomas' and rare conditions such as light chain crystal deposition disease. Kidney manifestations and heavy-chain deposition disease can also occur in plasma cell dyscrasias, emphasizing the role of IgG misfolding and aggregation. This minireview describes molecular mechanisms of IgG light-chain aggregation, as well as the consequences and therapeutic implications of IgG light chain misfolding in these disorders. By elucidating the mechanisms of IgG light chain misfolding and aggregation, researchers can identify specific molecular and cellular pathways. This knowledge opens the door to novel therapeutic targets, offering the potential for interventions that can either prevent the initial misfolding events, promote the proper folding and processing of immunoglobulins, or enhance the clearance of misfolded proteins and aggregates. These protein folding-related issues persist even after the successful elimination of the malignant B cells. Such targeted protein-folding therapies could significantly improve patients' quality of life and contribute to their recovery. Thus, a deep understanding of IgG light chain misfolding and its consequences not only sheds light on the complex biology of oncohematological dyscrasias but also opens the way for innovative treatment strategies that could transform patient care in these conditions, instilling hope and motivation in the healthcare professionals and researchers in this field.

The misfolding and aggregation of amyloid proteins are closely associated with a range of neurodegenerative diseases. Liquid-liquid phase separation (LLPS) can initiate the aggregation of proteins, indicating that LLPS may serve as an alternative pathway for the pathological aggregation of amyloid proteins. The co-occurrence of two or more amyloid pathologies has been observed in extensive pathophysiological studies and is linked to faster disease progression. The co-LLPS (also known as co-condensation) and co-aggregation of different disease-related proteins have been proposed as a potential molecular mechanism for combined neuropathology. Here, we reviewed the current state of knowledge regarding the co-aggregation and co-condensation of various amyloid proteins, including Aβ, tau, α-synuclein, TDP-43, FUS, and hnRNPA/B protein family, C9orf72 dipeptide repeats and prion protein. We briefly introduced the epidemiological correlation among different neurodegenerative diseases and specifically presented recent experimental findings about co-aggregation and co-condensation of two different amyloid proteins. Additionally, we discussed computational studies focusing on the molecular interactions between amyloid proteins to offer mechanistic insights into the co-LLPS and co-aggregation processes. This review provides an overview of the synergistic interactions between different disease-related proteins, which is helpful for understanding the mechanisms of combined neuropathology and developing targeted therapeutic strategies.

The phenomenon of Liquid-Liquid Phase Separation (LLPS) serves as a vital mechanism for the spatial organization of biomolecules, significantly influencing the elementary processes within the cellular milieu. Intrinsically disordered proteins, or proteins endowed with intrinsically disordered regions, are pivotal in driving this biophysical process, thereby dictating the formation of non-membranous cellular compartments. Compelling evidence has linked aberrations in LLPS to the pathogenesis of various neurodegenerative diseases, underscored by the disordered proteins’ proclivity to form pathological aggregates. This study meticulously evaluates the arsenal of contemporary experimental and computational methodologies dedicated to the examination of intrinsically disordered proteins within the context of LLPS. Through a discerning discourse on the capabilities and constraints of these investigative techniques, we unravel the intricate contributions of these ubiquitous proteins to LLPS and neurodegeneration. Moreover, we project a future trajectory for the field, contemplating on innovative research tools and their potential to elucidate the underlying mechanisms of LLPS, with the ultimate goal of fostering new therapeutic avenues for combating neurodegenerative disorders.

COVID-19 is a respiratory disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), but because the receptor protein of this virus can appear not only in the lungs and throat but also in various parts of the host's body, it causes different diseases. Recent observations have suggested that SARS-CoV-2 damages the central nervous system of patients in a manner similar to amyloid-associated neurodegenerative diseases such as Alzheimer's and Parkinson's. Neurodegenerative diseases are believed to be associated with the self-assembly of amyloid proteins and peptides. On the other hand, whole proteins or parts of them encoded by SARS-CoV-2 can form amyloid fibrils, which may play an important role in amyloid-related diseases. Motivated by this evidence, this mini-review discusses experimental and computational studies of SARS-CoV-2 proteins that can form amyloid aggregates. Liquid-Liquid Phase Separation (LLPS) is a dynamic and reversible process leading to the creation of membrane-less organelles within the cytoplasm, which is not bound by a membrane that concentrates specific types of biomolecules. These organelles play pivotal roles in cellular signaling, stress response, and the regulation of biomolecular condensates. Recently, LLPS of the Nucleocapsid (N) protein and SARS-CoV-2 RNA has been disclosed, but many questions about the phase separation mechanism and the formation of the virion core are still unclear. We summarize the results of this phenomenon and suggest potentially intriguing issues for future research.