Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1(G93A) motoneuron death through the Fas/NO pathway. In SOD1(G93A) mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1(G93A) motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS.
"Although the familial cases represent only $10% of all ALS cases, their characterization led to substantial insight into the pathophysiology of ALS (Sreedharan and Brown, 2013). Accumulating evidence from mouse models of motor neuron disease implicated synaptic pathology (Pun et al., 2006), mitochondrial dysfunction (Court and Coleman, 2012), calcium signalling impairment (Bernard-Marissal et al., 2012), endoplasmic reticulum (ER) stress (Saxena et al., 2009) and disturbances of axonal transport (Bilsland et al., 2010) as critical factors involved in motor neuron degeneration in ALS mouse models. "
"The expression of poly(GA) proteins causes neurotoxicity; this toxicity occurs in the absence of RNA foci, and is associated with impairment of the UPS and induction of ER stress. ER stress is believed to play an important role in several neurodegenerative diseases, including sporadic ALS [4, 26, 59, 69], and familiar ALS caused by mutations in Cu/Zn superoxide dismutase [8, 29, 48, 55] or vesicle-associated membrane protein-associated protein B [27, 45, 62]. Our data extend the list of diseases involving ER stress, and suggest that targeting the ER, using small molecules such as salubrinal and TUDCA, may be a promising therapeutic approach for c9FTD/ALS. "
[Show abstract][Hide abstract] ABSTRACT: The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
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"The activation of Fas (CD95) by its cognate ligand FasL commits cells to a death program through a caspase cascade (Peter et al., 2007). Interestingly, the activation of Fas triggers a death pathway in motoneurons that appeared restricted to this cell type (Raoul et al., 1999, 2002, 2006; Bernard-Marissal et al., 2012; Aebischer et al., 2013). Motoneurons expressing ALS-linked SOD1 mutations showed an increased susceptibility to Fas-mediated death through activation of a Fas/NO amplification loop (Raoul et al., 2002, 2006). "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.
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