Protein misfolding in neurodegenerative diseases: implications and strategies

Abstract

A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.

Anti‐inflammatory effects of hypoxia‐preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL‐37

“…An accumulation of evidence in recent years argues that reactive nitrogen species are among the major intracellular signal transducers that support pleiotropic responses that range from autophagy to death (51, 52). Dysregulation of autophagy is recognized as playing a central role in several neurodegenerative diseases (53, 54); however, its role in MS remains unclear (55). Although some early studies consider autophagy to be a mechanism of cell death, in recent years, has emerged in hypothesis as a useful mechanism for protecting cells from apoptosis (56).…”

Lysosomes as a therapeutic target

“…Increasing evidence thus implicates lysosomal (and autophagy) dysfunction in the pathogenesis of neuro degenerative disorders 62,63,127,128,130,191,192 . TFEB has received particular attention in this regard [193][194][195] , with recent data suggesting that TFEB is selectively lost in patients with AD (as well as ALS) 196 .…”

Recent advancement of light‐based single‐molecule approaches for studying biomolecules

“…This method is applicable to diverse biospecimens including cerebrospinal fluid, blood and tear fluid. In addition, single‐cell SiMPull allows for the quantification of variations in cell‐to‐cell protein expression levels (X. Wang, Park, Zeng, Jain, & Ha, ; Wedeking et al, ), which will help to understand why only a subpopulation of neurons show pathological phenotypes and develop target‐specific drugs (Sweeney et al, ). Controlled labeling, the use of smaller antibodies and uniform illumination will make SiMPull a powerful bioanalytical technique for high‐throughput quantitative analysis of endogenous proteins.…”