A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders

Abstract

Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.

Keywords: ER stress; mitochondria; neuropsychiatric disorders; protein aggregation; protein misfolding; proteostasis.

Figure 1.. Homeostatic pathways against protein misfolding and aggregation

Various mechanisms have been developed by the cell to protect against protein misfolding and aggregation. During and following mRNA translation, chaperones assist the nascent polypeptide chain via co-translational and post-translational mechanisms to fold properly into the correct “native” three-dimensional conformations. Once correctly folded, proteins can carry out their functions as monomeric proteins or multimeric protein complexes. However, they may become unfolded due to cellular stresses and require chaperones to return to their native conformations or shuttle for removal by proteasomal or autophagic degradation. If such misfolded proteins are not recognized by chaperones for refolding or degradation in a timely manner or the aforementioned cytoprotective mechanisms have been overwhelmed, these misfolded proteins may assume non-native conformations. Such non-native conformations remain as non-functional monomers or form soluble oligomers which could have functional properties different from their native monomeric counterparts. Furthermore, additional interacting proteins may be sequestered into these conformationally-altered species via heterotypic interactions and result in network-wide proteostatic disruptions.

Figure 2.. ER stress and aberrant overactivation of ER quality control pathways

Cell surface and secreted proteins are typically translated by ribosomes and imported into the ER in a co-translational manner. Misfolded proteins, due to pathologic mutations or reduced protein folding capacity in the ER, may disrupt ER-Golgi trafficking, which results in the ER accumulation of affected proteins, and increase ER-associated degradation (ERAD). Both of these could have negative effects as the expression and subcellular localization required for proper cell functions may be greatly impacted. Furthermore, the resulting ER stress consequently initiates the unfolded protein response (UPR), which triggers PERK, ATF6, and/or IRE1α-dependent pathways to enhance the ER protein folding capacity. Meanwhile, the overload in this protein folding capacity is reduced by suppressing global protein synthesis through the phosphorylation of eIF2α. Chronic eIF2α phosphorylation due to persistent ER stress may have detrimental effects as de novo protein synthesis is required for various types of synaptic plasticity and thereby disrupt the proper functioning of affected neurons.

Figure 3.. Involvement and vulnerability of mitochondria

Nuclear-encoded mitochondrial proteins are normally imported by the TOM/TIM complexes and processed into mature proteins by mitochondrial proteases. The mitochondrial unfolded protein response (UPR^mt) is triggered by a decline in mitochondrial protein import to compensate and correct for these changes. Recently, a process called MAGIC was shown to utilize the mitochondrial protein import machinery to transport misfolded and aggregated proteins into the mitochondria for degradation. This was further hypothesized as a means to ensure proper removal of misfolded and aggregated proteins as the mitochondria can be selectively removed via mitophagy. However, the import of problematic proteins into the mitochondria may also lead to mitochondrial dysfunctions if they are not properly dealt with in a timely manner. Critical mitochondrial functions such as Ca²⁺ homeostasis and ATP production may be disrupted and further disturb neuronal functions such as vesicular release and local translation, and could in turn greatly impact neurotransmission and synaptic plasticity, respectively.