Emerging Developments in Targeting Proteotoxicity in Neurodegenerative Diseases

Abstract

The most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, frontotemporal lobar degeneration, and the motor neuron diseases, with AD affecting approximately 6% of people aged 65 years and older, and PD affecting approximately 1% of people aged over 60 years. Specific proteins are associated with these neurodegenerative diseases, as determined by both immunohistochemical studies on post-mortem tissue and genetic screening, where protein misfolding and aggregation are key hallmarks. Many of these proteins are shown to misfold and aggregate into soluble non-native oligomers and large insoluble protein deposits (fibrils and plaques), both of which may exert a toxic gain of function. Proteotoxicity has been examined intensively in cell culture and in in vivo models, and clinical trials of methods to attenuate proteotoxicity are relatively new. Therapies to enhance cellular protein quality control mechanisms such as upregulation of chaperones and clearance/degradation pathways, as well as immunotherapies against toxic protein conformations, are being actively pursued. In this article, we summarize the common pathophysiology of neurodegenerative disease, and review therapies in early-phase clinical trials that target the proteotoxic component of several neurodegenerative diseases.

Fig. 1

The effects of proteotoxicity and cellular mechanisms that prevent it. A healthy neuron is capable of maintaining the stability of its functional proteome through the maintenance of proper folding fidelity, and degradation of misfolded proteins via autophagy and the ubiquitin-proteasome system. Misfolded proteins can also be rescued and refolded through interactions with chaperone proteins. If these mechanisms fail or become less effective beyond critical thresholds, unstable and misfolded proteins can accumulate and form inclusions, and/or aberrantly interact with molecules essential to key cellular pathways such as nucleocytoplasmic transport and mitochondrial functioning. The endoplasmic reticulum can also become chronically stressed. Misfolded proteins can prevent proper transport of RNA and proteins along axons, leading to axonal dysfunction and eventually cell death. Aberrant interactions involving intracellular or extracellular misfolded proteins or aggregates can impair synaptic transmission, which is essential for proper neuronal functioning. Finally, misfolded and aggregated proteins have the capability to propagate to nearby cells, leading to progressive neuronal degeneration