Visitor counter, Heat Map, Conversion tracking, Search Rank

  1. Amanda L Wright and Bryce Vissel.
    CAST your vote: is calpain inhibition the answer to ALS?. Journal of neurochemistry 137(2):140–1, April 2016.
    Abstract A publication in the Journal of Neurochemistry by Rao et al. (2016) suggests that the overexpression of the calpain inhibitor, calpastatin (CAST) rescues neuron loss and increases survival of the amyotrophic lateral sclerosis (ALS) mouse model, hSOD1G93A. The findings of Rao et al. (2016) provide an insight into the mechanisms that lead to neuronal loss in ALS and suggest a cell loss pathway common to several neurodegenerative disorders that may be therapeutically targeted. Here, we highlight the findings of Rao et al. (2016) and discuss some key considerations required prior to assessing the potential use of calpain inhibitors in the clinic. Read the highlighted article 'Calpastatin inhibits motor neuron death and increases survival in hSOD1(G93A) mice' on page 253.
    URL, DOI BibTeX

    @article{Wright2016,
    	abstract = "A publication in the Journal of Neurochemistry by Rao et al. (2016) suggests that the overexpression of the calpain inhibitor, calpastatin (CAST) rescues neuron loss and increases survival of the amyotrophic lateral sclerosis (ALS) mouse model, hSOD1G93A. The findings of Rao et al. (2016) provide an insight into the mechanisms that lead to neuronal loss in ALS and suggest a cell loss pathway common to several neurodegenerative disorders that may be therapeutically targeted. Here, we highlight the findings of Rao et al. (2016) and discuss some key considerations required prior to assessing the potential use of calpain inhibitors in the clinic. Read the highlighted article 'Calpastatin inhibits motor neuron death and increases survival in hSOD1(G93A) mice' on page 253.",
    	author = "Wright, Amanda L and Vissel, Bryce",
    	doi = "10.1111/jnc.13296",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	month = "apr",
    	number = 2,
    	pages = "140--1",
    	pmid = 27005822,
    	title = "{CAST your vote: is calpain inhibition the answer to ALS?}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/27005822",
    	volume = 137,
    	year = 2016
    }
    
  2. Mala V Rao, Jabbar Campbell, Arti Palaniappan, Asok Kumar and Ralph A Nixon.
    Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.. Journal of neurochemistry 137(2):253–65, 2016.
    Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, $\alpha$-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST over-expression in neurons attenuated pathological effects of TDP-43, $\alpha$-synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS. Read the Editorial Highlight for this article on page 140.
    URL, DOI BibTeX

    @article{Rao2016,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, $\alpha$-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST over-expression in neurons attenuated pathological effects of TDP-43, $\alpha$-synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS. Read the Editorial Highlight for this article on page 140.",
    	author = "Rao, Mala V and Campbell, Jabbar and Palaniappan, Arti and Kumar, Asok and Nixon, Ralph A",
    	doi = "10.1111/jnc.13536",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	month = "",
    	number = 2,
    	pages = "253--65",
    	pmid = 26756888,
    	title = "{Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26756888",
    	volume = 137,
    	year = 2016
    }
    
  3. Takenari Yamashita, Sayaka Teramoto and Shin Kwak.
    Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD. Neuroscience Research, December 2015.
    Abstract TAR DNA-binding protein-43 (TDP-43) pathology, which includes the presence of abnormal TDP-43-containing inclusions with a loss of nuclear TDP-43 in affected neurons, is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD). TDP-43 in the pathological brains and spinal cords of ALS/FTLD patients is abnormally fragmented and phosphorylated. It is believed that the generation of aggregation-prone TDP-43 fragments initiates TDP-43 pathology, and we previously reported that calpain has an important role in the generation of such aggregation-prone TDP-43 fragments. However, the role of phosphorylation in TDP-43 pathology has not been largely elucidated, despite previous observations that several kinases and their kinases are involved in TDP-43 phosphorylation. Here, we investigated the role of TDP-43 phosphorylation in the calpain-dependent cleavage of TDP-43 and found that phosphorylated, full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was. These results suggest that both phosphorylated and calpain-cleaved TDP-43 fragments persist intracellularly for a length of time that is sufficient for self-aggregation, thereby serving as seeds for inclusions.
    URL, DOI BibTeX

    @article{Yamashita2015,
    	abstract = "TAR DNA-binding protein-43 (TDP-43) pathology, which includes the presence of abnormal TDP-43-containing inclusions with a loss of nuclear TDP-43 in affected neurons, is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD). TDP-43 in the pathological brains and spinal cords of ALS/FTLD patients is abnormally fragmented and phosphorylated. It is believed that the generation of aggregation-prone TDP-43 fragments initiates TDP-43 pathology, and we previously reported that calpain has an important role in the generation of such aggregation-prone TDP-43 fragments. However, the role of phosphorylation in TDP-43 pathology has not been largely elucidated, despite previous observations that several kinases and their kinases are involved in TDP-43 phosphorylation. Here, we investigated the role of TDP-43 phosphorylation in the calpain-dependent cleavage of TDP-43 and found that phosphorylated, full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was. These results suggest that both phosphorylated and calpain-cleaved TDP-43 fragments persist intracellularly for a length of time that is sufficient for self-aggregation, thereby serving as seeds for inclusions.",
    	author = "Yamashita, Takenari and Teramoto, Sayaka and Kwak, Shin",
    	doi = "10.1016/j.neures.2015.12.006",
    	issn = 01680102,
    	journal = "Neuroscience Research",
    	month = "dec",
    	pmid = 26723245,
    	title = "{Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/26723245",
    	year = 2015
    }
    
  4. R Stifanese, M Averna, R De Tullio, M Pedrazzi, M Milanese, T Bonifacino, G Bonanno, F Salamino, S Pontremoli and E Melloni.
    Role of calpain-1 in the early phase of experimental ALS.. Archives of biochemistry and biophysics 562:1–8, November 2014.
    Abstract Elevation in [Ca(2+)]i and activation of calpain-1 occur in central nervous system of SOD1(G93A) transgenic mice model of amyotrophic lateral sclerosis (ALS), but few data are available about the early stage of ALS. We here investigated the level of activation of the Ca(2+)-dependent protease calpain-1 in spinal cord of SOD1(G93A) mice to ascertain a possible role of the protease in the aetiology of ALS. Comparing the events occurring in the 120 day old mice, we found that [Ca(2+)]i and activation of calpain-1 were also increased in the spinal cord of 30 day old mice, as indicated by the digestion of some substrates of the protease such as nNOS, $\alpha$II-spectrin, and the NR2B subunit of NMDA-R. However, the digestion pattern of these proteins suggests that calpain-1 may play different roles depending on the phase of ALS. In fact, in spinal cord of 30 day old mice, activation of calpain-1 produces high amounts of nNOS active species, while in 120 day old mice enhanced-prolonged activation of calpain-1 inactivates nNOS and down-regulates NR2B. Our data reveal a critical role of calpain-1 in the early phase and during progression of ALS, suggesting new therapeutic approaches to counteract its onset and fatal course.
    URL, DOI BibTeX

    @article{Stifanese2014,
    	abstract = "Elevation in [Ca(2+)]i and activation of calpain-1 occur in central nervous system of SOD1(G93A) transgenic mice model of amyotrophic lateral sclerosis (ALS), but few data are available about the early stage of ALS. We here investigated the level of activation of the Ca(2+)-dependent protease calpain-1 in spinal cord of SOD1(G93A) mice to ascertain a possible role of the protease in the aetiology of ALS. Comparing the events occurring in the 120 day old mice, we found that [Ca(2+)]i and activation of calpain-1 were also increased in the spinal cord of 30 day old mice, as indicated by the digestion of some substrates of the protease such as nNOS, $\alpha$II-spectrin, and the NR2B subunit of NMDA-R. However, the digestion pattern of these proteins suggests that calpain-1 may play different roles depending on the phase of ALS. In fact, in spinal cord of 30 day old mice, activation of calpain-1 produces high amounts of nNOS active species, while in 120 day old mice enhanced-prolonged activation of calpain-1 inactivates nNOS and down-regulates NR2B. Our data reveal a critical role of calpain-1 in the early phase and during progression of ALS, suggesting new therapeutic approaches to counteract its onset and fatal course.",
    	author = "Stifanese, R and Averna, M and {De Tullio}, R and Pedrazzi, M and Milanese, M and Bonifacino, T and Bonanno, G and Salamino, F and Pontremoli, S and Melloni, E",
    	doi = "10.1016/j.abb.2014.08.006",
    	issn = "1096-0384",
    	journal = "Archives of biochemistry and biophysics",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Calcium,Calcium: metabolism,Calpain,Calpain: metabolism,Disease Models, Animal,Disease Progression,Humans,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: metabolism,Nitric Oxide Synthase Type I,Nitric Oxide Synthase Type I: genetics,Nitric Oxide Synthase Type I: metabolism,Proteolysis,Receptors, N-Methyl-D-Aspartate,Receptors, N-Methyl-D-Aspartate: genetics,Receptors, N-Methyl-D-Aspartate: metabolism,Spinal Cord,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "nov",
    	pages = "1--8",
    	pmid = 25151305,
    	title = "{Role of calpain-1 in the early phase of experimental ALS.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25151305",
    	volume = 562,
    	year = 2014
    }
    
  5. Takenari Yamashita and Shin Kwak.
    [Calpain plays a crucial role in TDP-43 pathology].. Rinshō shinkeigaku = Clinical neurology 54(12):1151–4, January 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease affecting healthy middle-aged individuals. Mislocalization of TAR DNA binding protein of 43 kDa (TDP-43) or TDP-43 pathology observed in the spinal motor neurons is the pathological hallmark of ALS. The mechanism generating TDP-43 pathology remained uncertain. Several reports suggested that cleavage of TDP-43 into aggregation-prone fragments might be the earliest event. Therefore, elucidation of the protease(s) that is responsible for TDP-43 cleavage in the motor neurons is awaited. ALS-specific molecular abnormalities other than TDP-43 pathology in the motor neurons of sporadic ALS patients include inefficient RNA editing at the GluA2 glutamine/arginine (Q/R) site, which is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2). We have developed the conditional ADAR2 knockout (AR2) mice, in which the ADAR2 gene is targeted in motor neurons. We found that Ca(2+)-dependent cysteine protease calpain cleaved TDP-43 into aggregation-prone fragments, which initiated TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca(2+)-permeable AMPA receptors. Here we summarized the molecular cascade leading to TDP-43 pathology observed in the motor neurons of AR2 mice and discussed possible roles of dysregulation of calpain-dependent cleavage of TDP-43 in TDP-43 pathology observed in neurological diseases in general.
    URL, DOI BibTeX

    @article{Yamashita2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease affecting healthy middle-aged individuals. Mislocalization of TAR DNA binding protein of 43 kDa (TDP-43) or TDP-43 pathology observed in the spinal motor neurons is the pathological hallmark of ALS. The mechanism generating TDP-43 pathology remained uncertain. Several reports suggested that cleavage of TDP-43 into aggregation-prone fragments might be the earliest event. Therefore, elucidation of the protease(s) that is responsible for TDP-43 cleavage in the motor neurons is awaited. ALS-specific molecular abnormalities other than TDP-43 pathology in the motor neurons of sporadic ALS patients include inefficient RNA editing at the GluA2 glutamine/arginine (Q/R) site, which is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2). We have developed the conditional ADAR2 knockout (AR2) mice, in which the ADAR2 gene is targeted in motor neurons. We found that Ca(2+)-dependent cysteine protease calpain cleaved TDP-43 into aggregation-prone fragments, which initiated TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca(2+)-permeable AMPA receptors. Here we summarized the molecular cascade leading to TDP-43 pathology observed in the motor neurons of AR2 mice and discussed possible roles of dysregulation of calpain-dependent cleavage of TDP-43 in TDP-43 pathology observed in neurological diseases in general.",
    	author = "Yamashita, Takenari and Kwak, Shin",
    	doi = "10.5692/clinicalneurol.54.1151",
    	issn = "1882-0654",
    	journal = "Rinshō shinkeigaku = Clinical neurology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Animals,Calcium Signaling,Calcium Signaling: genetics,Calcium Signaling: physiology,Calpain,Calpain: physiology,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Disease Models, Animal,Humans,Mice,Mice, Knockout,Motor Neurons,Motor Neurons: metabolism,RNA Editing,Receptors, AMPA,Receptors, AMPA: physiology,Spinal Cord,Spinal Cord: cytology",
    	month = "jan",
    	number = 12,
    	pages = "1151--4",
    	pmid = 25672733,
    	title = "{[Calpain plays a crucial role in TDP-43 pathology].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25672733",
    	volume = 54,
    	year = 2014
    }
    
  6. Roberta De Tullio, Monica Averna, Marco Pedrazzi, Bianca Sparatore, Franca Salamino, Sandro Pontremoli and Edon Melloni.
    Differential regulation of the calpain-calpastatin complex by the L-domain of calpastatin.. Biochimica et biophysica acta 1843(11):2583–91, 2014.
    Abstract Here we demonstrate that the presence of the L-domain in calpastatins induces biphasic interaction with calpain. Competition experiments revealed that the L-domain is involved in positioning the first inhibitory unit in close and correct proximity to the calpain active site cleft, both in the closed and in the open conformation. At high concentrations of calpastatin, the multiple EF-hand structures in domains IV and VI of calpain can bind calpastatin, maintaining the active site accessible to substrate. Based on these observations, we hypothesize that two distinct calpain-calpastatin complexes may occur in which calpain can be either fully inhibited (I) or fully active (II). In complex II the accessible calpain active site can be occupied by an additional calpastatin molecule, now a cleavable substrate. The consequent proteolysis promotes the accumulation of calpastatin free inhibitory units which are able of improving the capacity of the cell to inhibit calpain. This process operates under conditions of prolonged [Ca(2+)] alteration, as seen for instance in Familial Amyotrophic Lateral Sclerosis (FALS) in which calpastatin levels are increased. Our findings show that the L-domain of calpastatin plays a crucial role in determining the formation of complexes with calpain in which calpain can be either inhibited or still active. Moreover, the presence of multiple inhibitory domains in native full-length calpastatin molecules provides a reservoir of potential inhibitory units to be used to counteract aberrant calpain activity.
    URL, DOI BibTeX

    @article{DeTullio2014,
    	abstract = "Here we demonstrate that the presence of the L-domain in calpastatins induces biphasic interaction with calpain. Competition experiments revealed that the L-domain is involved in positioning the first inhibitory unit in close and correct proximity to the calpain active site cleft, both in the closed and in the open conformation. At high concentrations of calpastatin, the multiple EF-hand structures in domains IV and VI of calpain can bind calpastatin, maintaining the active site accessible to substrate. Based on these observations, we hypothesize that two distinct calpain-calpastatin complexes may occur in which calpain can be either fully inhibited (I) or fully active (II). In complex II the accessible calpain active site can be occupied by an additional calpastatin molecule, now a cleavable substrate. The consequent proteolysis promotes the accumulation of calpastatin free inhibitory units which are able of improving the capacity of the cell to inhibit calpain. This process operates under conditions of prolonged [Ca(2+)] alteration, as seen for instance in Familial Amyotrophic Lateral Sclerosis (FALS) in which calpastatin levels are increased. Our findings show that the L-domain of calpastatin plays a crucial role in determining the formation of complexes with calpain in which calpain can be either inhibited or still active. Moreover, the presence of multiple inhibitory domains in native full-length calpastatin molecules provides a reservoir of potential inhibitory units to be used to counteract aberrant calpain activity.",
    	author = "{De Tullio}, Roberta and Averna, Monica and Pedrazzi, Marco and Sparatore, Bianca and Salamino, Franca and Pontremoli, Sandro and Melloni, Edon",
    	doi = "10.1016/j.bbamcr.2014.07.002",
    	issn = "0006-3002",
    	journal = "Biochimica et biophysica acta",
    	month = "",
    	number = 11,
    	pages = "2583--91",
    	pmid = 25026177,
    	title = "{Differential regulation of the calpain-calpastatin complex by the L-domain of calpastatin.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25026177",
    	volume = 1843,
    	year = 2014
    }
    
  7. Takenari Yamashita and Shin Kwak.
    The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.. Brain research, 2013.
    Abstract TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general. This article is part of a Special Issue entitled RNA Metabolism 2013.
    URL, DOI BibTeX

    @article{Yamashita2013,
    	abstract = "TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general. This article is part of a Special Issue entitled RNA Metabolism 2013.",
    	author = "Yamashita, Takenari and Kwak, Shin",
    	doi = "10.1016/j.brainres.2013.12.011",
    	issn = "1872-6240",
    	journal = "Brain research",
    	month = "",
    	pmid = 24355598,
    	title = "{The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24355598",
    	year = 2013
    }
    
  8. Takenari Yamashita, Takuto Hideyama, Kosuke Hachiga, Sayaka Teramoto, Jiro Takano, Nobuhisa Iwata, Takaomi C Saido and Shin Kwak.
    A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.. Nature communications 3:1307, 2012.
    Abstract Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize 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 Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-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 Ca2+-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.
    URL, DOI BibTeX

    @article{Yamashita2012,
    	abstract = "Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize 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 Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-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 Ca2+-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.",
    	author = "Yamashita, Takenari and Hideyama, Takuto and Hachiga, Kosuke and Teramoto, Sayaka and Takano, Jiro and Iwata, Nobuhisa and Saido, Takaomi C and Kwak, Shin",
    	doi = "10.1038/ncomms2303",
    	issn = "2041-1723",
    	journal = "Nature communications",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Blotting, Western,Calpain,Calpain: physiology,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,DNA-Binding Proteins: physiology,HeLa Cells,Humans,Mice,Mice, Knockout,Mice, Mutant Strains,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Motor Neurons: physiology,Up-Regulation,Up-Regulation: physiology",
    	month = "",
    	pages = 1307,
    	pmid = 23250437,
    	title = "{A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23250437",
    	volume = 3,
    	year = 2012
    }