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.

Keywords: Biomarkers; Chaperones; Drug discovery; Mouse models; Neurodegeneration; Proteostasis.

Fig. 1

Mechanisms involved in protein misfolding & therapeutic targets. A newly synthesized protein is stabilized by endogenous chaperone proteins. Under normal conditions abnormal protein aggregates (misfolded proteins) are degraded and/or cleared extracellularly, undergo autophagy or are degraded with the aid of the cellular proteasome. In cases of abnormality and misfolding of proteins (such as those present in many neurological diseases) post translational modification inhibitors, protein cleavage inhibitors and extrinsic molecular chaperones have been used in attempts to curtail or correct protein misfolding. In addition, post translational approaches to address and combat the presence of misfolded proteins include agonists that attempt to activate endogenous clearance pathways as well as the introduction of recombinant antibodies to work against the rogue protein