Regulation of protein homeostasis in neurodegenerative diseases: the role of coding and non-coding genes

Abstract

Protein homeostasis is fundamental for cell function and survival, because proteins are involved in all aspects of cellular function, ranging from cell metabolism and cell division to the cell’s response to environmental challenges. Protein homeostasis is tightly regulated by the synthesis, folding, trafficking and clearance of proteins, all of which act in an orchestrated manner to ensure proteome stability. The protein quality control system is enhanced by stress response pathways, which take action whenever the proteome is challenged by environmental or physiological stress. Aging, however, damages the proteome, and such proteome damage is thought to be associated with aging-related diseases. In this review, we discuss the different cellular processes that define the protein quality control system and focus on their role in protein conformational diseases. We highlight the power of using small organisms to model neurodegenerative diseases and how these models can be exploited to discover genetic modulators of protein aggregation and toxicity. We also link findings from small model organisms to the situation in higher organisms and describe how some of the genetic modifiers discovered in organisms such as worms are functionally conserved throughout evolution. Finally, we demonstrate that the non-coding genome also plays a role in maintaining protein homeostasis. In all, this review highlights the importance of protein and RNA homeostasis in neurodegenerative diseases.

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

“…Among these 98 proteins, 29 are associated with neurodegenerative diseases, 7 are associated with cardiovascular diseases, 6 are associated with diseases of the immune system, and 10 are associated with cancer. While the role of protein aggregation has been extensively studied in the context of proteostasis and neurodegenerative diseases, the observations reported in the Supporting Information Table S1 show that protein misfolding and aggregation are associated with several other types of human maladies. Consistent with these observations, evidence suggesting a role for aggregation in cancer is emerging .…”

“…Native conformations of proteins are maintained by a balance between entropy and enthalpy under physiological conditions by avoiding potential intermediates and metastable states, which are prone to misfolding and aggregation. Proteostasis is therefore controlled in each cell by strict regulation of biogenesis, folding (chaperone assisted or otherwise), trafficking and degradation . Even slight disturbances in this regulation can lead to accumulation of misfolded protein aggregates and consequently result in diseases.…”

“…This survey reveals that several sequence‐structural optimization strategies have minimized deleterious consequences due to the presence of APRs in the human proteome. Many of these strategies have been described by previous studies on general properties of the APRs . However, some of them are new.…”

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

“…In addition, there is evidence that the cellular dysfunction of ER Stress has consequences for neurodegeneration and progression of diseases such as AD (J. H. Lin, et al, 2008; Riederer, et al, 2011; Sin & Nollen, 2015). Thus, protecting against the trio of ER Stress, ROS and mitochondrial dysfunction is the unifying action that allows the sEHI to be beneficial in a wider variety of pathological conditions.…”

Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation

“…The hallmark of many neurodegenerative disorders is the presence of protein aggregates in different brain areas of affected patients (Soto, 2003). These insoluble macromolecular structures are enriched in aggregation-prone proteins that—by exposing certain regions of their amino acid sequences—associate in an aberrant manner with other proteins, thereby hampering normal cellular function (Eisenberg and Jucker, 2012, Olzscha et al., 2011; also reviewed in Chiti and Dobson, 2009, Sin and Nollen, 2015). It is not yet clear, however, whether these protein aggregates are actually a cause or a consequence of the disease.…”