Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions.

UNLABELLED: The PKR-like endoplasmic reticulum kinase (PERK) pathway of the unfolded protein response (UPR) is protective against toxic accumulations of misfolded proteins in the endoplasmic reticulum, but is thought to drive cell death via the transcription factor, CHOP. However, in many cell types, CHOP is an obligate step in the PERK pathway, which frames the conundrum of a prosurvival pathway that kills cells. Our laboratory and others have previously demonstrated the prosurvival activity of the PERK pathway in oligodendrocytes. In the current study, we constitutively overexpress CHOP in myelinating cells during development and into adulthood under normal or UPR conditions. We show that this transcription factor does not drive apoptosis. Indeed, we observe no detriment in mice at multiple levels from single cells to mouse behavior and life span. In light of these data and other studies, we reinterpret PERK pathway function in the context of a stochastic vulnerability model, which governs the likelihood that cells undergo cell death upon cessation of UPR protection and while attempting to restore homeostasis. SIGNIFICANCE STATEMENT: Herein, we tackle the biggest controversy in the UPR literature: the function of the transcription factor CHOP as a protective or a prodeath factor. This manuscript is timely in light of the 2014 Lasker award for the UPR. Our in vivo data show that CHOP is not a prodeath protein, and we demonstrate that myelinating glial cells function normally in the presence of high CHOP expression from development to adulthood. Further, we propose a simplified view of UPR-mediated cell death after CHOP induction. We anticipate our work may turn the tide of the dogmatic view of CHOP and cause a reinvestigation of its function in different cell types. Accordingly, we believe our work will be a watershed for the UPR field.

Potential For Cell-mediated Immune Responses In Mouse Models Of Pelizaeus-Merzbacher Disease.

Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary inflammatory responses inside and outside of the nervous system. In this study, we show that the metabolic stress pathway known as the unfolded protein response (UPR) leads to secondary activation of the immune system. First, we observe innate immune system activation in autopsy specimens from Pelizaeus-Merzbacher disease (PMD) patients and mouse models stemming from PLP1 gene mutations. Second, missense mutations in mildly- and severely-affected Plp1-mutant mice exhibit immune-associated expression profiles with greater disease severity causing an increasingly proinflammatory environment. Third and unexpectedly, we find little evidence for dysregulated expression of major antioxidant pathways, suggesting that the unfolded protein and oxidative stress responses are separable. Together, these data show that UPR activation can precede innate and/or adaptive immune system activation and that neuroinflammation can be titrated by metabolic stress in oligodendrocytes. Whether-or-not such activation leads to autoimmune disease in humans is unclear, but the case report of steroid-mitigated symptoms in a PMD patient initially diagnosed with multiple sclerosis lends support.

Claudin Proteins And Neuronal Function.

The identification and characterization of the claudin family of tight junction (TJ) proteins in the late 1990s ushered in a new era for research into the molecular and cellular biology of intercellular junctions. Since that time, TJs have been studied in the contexts of many diseases including deafness, male infertility, cancer, bacterial invasion and liver and kidney disorders. In this review, we consider the role of claudins in the nervous system focusing on the mechanisms by which TJs in glial cells are involved in neuronal function. Electrophysiological evidence suggests that claudins may operate in the central nervous system (CNS) in a manner similar to polarized epithelia. We also evaluate hypotheses that TJs are the gatekeepers of an immune-privileged myelin compartment and that TJs emerged during evolution to form major adhesive forces within the myelin sheath. Finally, we consider the implications of CNS myelin TJs in the contexts of behavioral disorders (schizophrenia) and demyelinating/hypomyelinating diseases (multiple sclerosis and the leukodystrophies), and explore evidence of a possible mechanism governing affective disorder symptoms in patients with white matter abnormalities.