A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice

Saxena, Smita; Cabuy, Erik; Caroni, Pico

doi:10.1038/nn.2297

Cited by 531 publications

(586 citation statements)

References 46 publications

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“…eR stress is now established as a key pathway to cell death in aLS [7,8,23,31]. Mutant SOD1 induces eR stress [6] and Golgi fragmentation [26] in neuronal cell cultures, and we now show that aggregated SOD1 Wt induces UPR and Golgi fragmentation similar to mutant SOD1.…”

Section: Discussionsupporting

confidence: 52%

“…however, endoplasmic reticulum (eR) stress and fragmentation of the Golgi apparatus are well-described features in human aLS patients as well as in animal and cellular disease models [6][7][8][9]. eR stress is triggered initially in the most vulnerable motor neurons during early disease stages in several lines of transgenic mutant SOD1 mice, thus implying an active role in neurodegeneration [8].…”

Section: Introductionmentioning

confidence: 99%

“…eR stress is triggered initially in the most vulnerable motor neurons during early disease stages in several lines of transgenic mutant SOD1 mice, thus implying an active role in neurodegeneration [8].…”

Section: Introductionmentioning

confidence: 99%

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Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ERGolgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ERGolgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. Abstract amyotrophic lateral sclerosis (aLS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of aLS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. aLS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. however, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of aLS pathology. Similarly, whilst dysfunction to the eR-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial aLS, it remains unclear whether misfolded, wildtype SOD1 triggers eR-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the eR-Golgi apparatus, leading to Golgi fragmentation, induction of eR stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces eR-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. hence extracellu...

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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“…Examples for neurodegenerative diseases for which a UPR contribution has been proposed include Parkinson's disease [78], Huntington's disease [79], and AD [80]. More specifically, a role of axonal ER stress or UPR has been is suggested by the finding of elevated ER stress markers within motorneuron axons in a mouse model for ALS [81], and in response to axotomy [82] or ischemic injury [83]. Despite this evidence it is not known whether the UPR or other eIF2α kinases are activated within axons upon exposure to Aβ or whether their activation necessarily leads to degeneration of the neuronal cell bodies.…”

Section: Stress Signaling In Axonsmentioning

confidence: 99%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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“…Indeed, it is likely that Ca 2 þ influx though N-methyl-D-aspartate receptors and other Ca 2 þ sources may have a central role in TDP-43 mislocalization in ischaemic and traumatic brain injury. Although pathogenic roles of endoplasmic reticulum stress and mitochondrial damage are implied in ALS 47,48 , a role for internal Ca 2 þ storage vesicles in TDP-43 pathology, however, has not been demonstrated. TDP-43 pathology is rarely, if ever, observed in the motor neurons of patients with SOD1-associated ALS or in SOD1 Tg animals 24,49 .…”

Section: )mentioning

confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

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Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

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A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice

Cited by 531 publications

References 46 publications

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

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