The unfolded protein response (UPR) is a homeostatic mechanism by which cells regulate levels of misfolded proteins in the endoplasmic reticulum (ER). Although it is well characterized in non-neuronal cells, a proliferation of papers over the past few years has revealed a key role for the UPR in normal neuronal function and as an important driver of neurodegenerative diseases. A complex scenario is emerging in which distinct UPR signalling modules have specific and even opposite effects on neurodegeneration depending on the disease context. Here, we provide an overview of the most recent findings addressing the biological relevance of ER stress in the nervous system.

http://repositorio.uchile.cl/bitstream/handle/2250/129356/Disturbance%20of%20endoplasmic%20reticulum.pdf?sequence=1

Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases

In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.

The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications.

The endoplasmic reticulum (ER) as an intracellular Ca(2+) store not only sets up cytosolic Ca(2+) signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca(2+) depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca(2+) may no longer sustain essential cell functions. On the other hand, loss of luminal Ca(2+) causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca(2+) depletion.

/pdf/endoplasmic-reticulum-calcium-depletion-and-disease-1erllmrcpb.pdf

Endoplasmic-Reticulum Calcium Depletion and Disease

Neuronal ceroid lipofuscinoses

The mechanisms of lysophosphatidylcholine in the development of diseases

Numerous proteins undergo modification by palmitic acid (S-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. Although palmitoylation is an essential modification, these proteins must also undergo depalmitoylation for their degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes palmitate residues facilitating the degradation of these proteins. Thus, inactivating mutations in the PPT1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood. Although rapidly progressing brain atrophy is the most dramatic pathological manifestation of INCL, the molecular mechanism(s) remains unclear. Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal. Further, we demonstrate that the level of growth-associated protein-43 (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in the abnormal accumulation of this protein in the ER. Consistent with these results, we found evidence for the activation of unfolded protein response (UPR) marked by elevated levels of phosphorylated translation initiation factor, eIF2alpha, increased expression of chaperone proteins such as glucose-regulated protein-78 and activation of caspase-12, a cysteine proteinase in the ER, mediating caspase-3 activation and apoptosis. Our results, for the first time, link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration in INCL and identify potential targets for therapeutic intervention in this uniformly fatal disease.

Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL

MS#HMG-2005W-00911.R1 (Zhang, Z. et al) Palmitoyl-Protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL

In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A2 (cPLA2) in the PPT1-KO mouse brain, is a ‘lipid signal’ for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA2-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.

/pdf/production-of-lysophosphatidylcholine-by-cpla2-in-the-brain-dwijo60nb1.pdf

Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration

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Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL

MS#HMG-2005W-00911.R1 (Zhang, Z. et al) Palmitoyl-Protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL

Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration