The Proteostasis Network: A Global Therapeutic Target for Neuroprotection after Spinal Cord Injury

Abstract

Proteostasis (protein homeostasis) is critical for cellular as well as organismal survival. It is strictly regulated by multiple conserved pathways including the ubiquitin-proteasome system, autophagy, the heat shock response, the integrated stress response, and the unfolded protein response. These overlapping proteostasis maintenance modules respond to various forms of cellular stress as well as organismal injury. While proteostasis restoration and ultimately organism survival is the main evolutionary driver of such a regulation, unresolved disruption of proteostasis may engage pro-apoptotic mediators of those pathways to eliminate defective cells. In this review, we discuss proteostasis contributions to the pathogenesis of traumatic spinal cord injury (SCI). Most published reports focused on the role of proteostasis networks in acute/sub-acute tissue damage post-SCI. Those reports reveal a complex picture with cell type- and/or proteostasis mediator-specific effects on loss of neurons and/or glia that often translate into the corresponding modulation of functional recovery. Effects of proteostasis networks on such phenomena as neuro-repair, post-injury plasticity, as well as systemic manifestations of SCI including dysregulation of the immune system, metabolism or cardiovascular function are currently understudied. However, as potential interventions that target the proteostasis networks are expected to impact many cell types across multiple organ systems that are compromised after SCI, such therapies could produce beneficial effects across the wide spectrum of highly variable human SCI.

Uremic plasma proteins accumulate in peripheral blood mononuclear leukocytes inducing apoptosis: insights in the immuno-proteostasis response of chronic kidney disease.

“…Our ndings demonstrate that such an aberrant cell response is associated with the endocytosis of plasma proteins, a process that brings uremic material from the external milieu to mobilize back to the ER of mononuclear leukocytes by retrograde transport (58), and apparently to the autophagy pathway, for removal/recycling. In this respect, the capability of these cell proteostasis pathways to interact with the extracellular environment is fundamental to control protein damage and aggregations at the systemic level (59,60), but their hyperactivation in CKD make the IPR and its attempt to correct the uremic proteostasis defect a futile, and even self-defeating, process. Indeed, IPR is lethal to PBL, leading to aberrant/premature apoptosis through increased ROS generation and JNK/c-Jun signaling.…”

Induction of Vesicular Trafficking and JNK-Mediated Apoptotic Signaling in Mononuclear Leukocytes Marks the Immuno-Proteostasis Response to Uremic Proteins

“…Regardless of the endocytosis mechanism (recently reviewed in [46]), the fact that uremic material from the external milieu can mobilize to mononuclear leukocytes implies the activation of retrograde transport mechanisms by the vesicular system of these cells. This is a para-physiological process that can contribute to systemic proteostasis [47,48] involving molecular chaperones [49] active in capturing unfolded or misfolded proteins in the ex-tracellular compartments and leading them to intracellular proteostasis modules, essentially the ER for protein repair or lysosomes and autophagosomes for proteolysis and removal/recycling [50]. Uremic toxins may hardly interfere with these processes, leading to an increased demand of proteostasis in different tissues and systems, including immune cells.…”

Linear ubiquitin chains remodel the proteome and influence the levels of hundreds of regulators inDrosophila

“…Lastly, since ubiquitin-mediated protein quality control is a bona fide protective molecular mechanism in neurodegenerative diseases (39)(40)(41)(42)(43), we assessed changes to neurodegeneration pathway proteins upon expression of the UBX and UBX_GG constructs (figure 5B). Although the linear UB constructs were ubiquitously expressed and not targeted to the nervous system, we identified changes in abundance of proteins that have been shown to be neuroprotective in distinct neurodegenerative pathologies, most notably, 'cry','tefu', and 'Nazo'.…”