In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasm... more In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasmic reticulum (ER) and Golgi outposts (GOPs), whose role in neurotransmitter receptor trafficking is poorly understood. γ-aminobutyric acid (GABA) type B metabotropic receptors (GABABRs) regulate the efficacy of synaptic transmission throughout the brain. Their plasma membrane availability is controlled by mechanisms involving an ER retention motif and assembly-dependent ER export. Thus, they constitute an ideal molecular model to study ER trafficking, but the extent to which the dendritic ER participates in GABABR biosynthesis has not been thoroughly explored. Here, we show that GABAB1 localizes preferentially to the ER in dendrites and moves long distances within this compartment. Not only diffusion but also microtubule and dynein-dependent mechanisms control dendritic ER transport. GABABRs insert throughout the somatodendritic plasma membrane but dendritic post-ER carriers containing G...
Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathoph... more Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed.
Alzheimer's disease (AD) is a progressive neurode... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.
The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and matur... more The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and maturation of around one-third of the total proteome. Accumulation of misfolded proteins in the ER lumen engages a signal transduction pathway known as unfolded protein response (UPR) that feedback to recover ER homeostasis or to trigger apoptosis of irreversible damaged cells. The UPR is initiated by three main stress sensors including protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein 1α (IRE1α), which reprogram the genome through the control of downstream transcription factors. In this article, the authors have reviewed most relevant studies uncovering the physiological function of the UPR in different organs and tissues based on the phenotypes observed after genetic manipulation of the pathway in vivo. Biomedical applications of targeting the UPR on a disease context are also discussed.
In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasm... more In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasmic reticulum (ER) and Golgi outposts (GOPs), whose role in neurotransmitter receptor trafficking is poorly understood. γ-aminobutyric acid (GABA) type B metabotropic receptors (GABABRs) regulate the efficacy of synaptic transmission throughout the brain. Their plasma membrane availability is controlled by mechanisms involving an ER retention motif and assembly-dependent ER export. Thus, they constitute an ideal molecular model to study ER trafficking, but the extent to which the dendritic ER participates in GABABR biosynthesis has not been thoroughly explored. Here, we show that GABAB1 localizes preferentially to the ER in dendrites and moves long distances within this compartment. Not only diffusion but also microtubule and dynein-dependent mechanisms control dendritic ER transport. GABABRs insert throughout the somatodendritic plasma membrane but dendritic post-ER carriers containing G...
Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathoph... more Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed.
Alzheimer's disease (AD) is a progressive neurode... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.
The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and matur... more The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and maturation of around one-third of the total proteome. Accumulation of misfolded proteins in the ER lumen engages a signal transduction pathway known as unfolded protein response (UPR) that feedback to recover ER homeostasis or to trigger apoptosis of irreversible damaged cells. The UPR is initiated by three main stress sensors including protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein 1α (IRE1α), which reprogram the genome through the control of downstream transcription factors. In this article, the authors have reviewed most relevant studies uncovering the physiological function of the UPR in different organs and tissues based on the phenotypes observed after genetic manipulation of the pathway in vivo. Biomedical applications of targeting the UPR on a disease context are also discussed.
Uploads