Dados do Trabalho

Título

Molecular Mechanisms in Neurodegeneration and Protein Accumulation: A​ ​Review

Resumo

Introduction
The abnormal accumulation of proteins is a common feature of neurodegenerative diseases. Novel information regarding the mechanism of aggregation include dysfunction of proteins involved in membraneless organelles formation, which have a chemical structure that is prone to aggregation. Once assembled, these aggregates spread in the central nervous system through a prion-like mechanism that involves the exportation of seeding nuclei to nearby neurons.

Objective
This work aims to review the main protein misfolding mechanisms involved in neurodegeneration, as well as to explain the recent prion-like spreading of such misfolding patterns throughout the central nervous system. Moreover, this review dives into chemical structure particularities of some common proteins identified in neurodegenerative diseases.

Methods
Articles produced between 2010 and 2022 were searched using keywords related to the field of study. The selection of included studies was based on whether the papers' theme was neurodegeneration, protein aggregation and/or prion-like mechanism of spreading.

Results
The reviewed studies showed that the mechanisms of protein aggregation seem to be closely related to membraneless organelles dysfunction. Such organelles have important physiological functions. However, under certain conditions, they might form irreversible solid aggregates, whose toxicity is related to neuronal dysfunction and death. The studied proteins have low complexity domains that predispose them to misfold, with a particular chemical structure identified.
Moreover, we discussed the prion-like mechanism theory for neurodegeneration spreading, allowing novel approaches to this group of diseases. This theory states that transference of prionic nuclei may occur among neural cells, which would induce protein misfolding and aggregation in naive cells.

Conclusion
Abnormal accumulation of protein aggregates in neurodegenerative disorders has been extensively studied in the last years. Although intrinsically disordered regions have been evolutionarily selected for the assembly membraneless organelles, they are related to toxic protein aggregation within neurons. Furthermore, the prion-like spreading mechanism of such aggregates seems to play a role in the dissemination of neurodegeneration. Identifying the mechanisms and structures involved in this process might contribute to the development of new therapeutic approaches against such disorders.

Palavras Chave

Neurodegeneration; protein accumulation, prion, prion-like, protein aggregates, membraneless organelles, tau, TDP-43, beta-amyloid, protein phase separation, review, narrative review

Área

Neurologia Cognitiva E Do Envelhecimento