Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Abstract

Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

Keywords: amyotrophic lateral sclerosis (ALS); autophagy; chaperones; endoplasmic reticulum-associated degradation (ERAD); frontotemporal dementia (FTD); protein quality control; ubiquitin–proteasome system (UPS); unfolded protein response.

Figure 1

Illustrative representation of protein quality control mechanisms in the cell. Following translation, newly synthesized nascent polypeptides are constantly at risk of misfolding and aggregation. Chaperones facilitate folding of proteins or refolding misfolded proteins. Approximately one-third of newly folded proteins transit through the endoplasmic reticulum (ER)–Golgi pathway for post-translational modification and secretion. Proteins which are not correctly folded are recognized by ER-associated degradation (ERAD), targeted for ubiquitin–proteasome degradation, autophagy, or a smaller proportion are degraded by chaperone mediated autophagy (CMA). In case of protein aggregation, stress granules (SGs) form transiently and are cleared through macroautophagy.

Figure 2

Schematic diagram illustrating genetic overlap of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The genes are distributed according to their mutation frequency in familial forms of ALS and FTD. The available evidence supports the existence of a disease continuum, with mutations in the same genes discovered in patients with FTD (blue), ALS (orange), or ALS/FTD (red).

Figure 3

Disruption to proteostasis mechanisms in ALS/FTD. Aberrant subcellular localization of misfolded proteins, and their associated effects on the proteostasis network, including proteasome dysfunction, autophagy dysregulation, ER to Golgi transport inhibition and ER stress. Aberrant DNA/RNA metabolism is also implicated as an important pathophysiological mechanism in ALS.