PMC:6610326 / 48065-49784
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"TDP-43 pathology may then propagate through corticofugal axons to the spinal cord and regions of the brain (Braak et al., 2013; Eisen et al., 2017) in a time-dependant and region-specific manner (Brettschneider et al., 2013), consistent with the dying forward hypothesis (Figure 3). This sequential pattern of TDP-43 dissemination is consistent with the hypothesis that TDP-43 pathology is propagated synaptically from cell to cell (Brundin et al., 2010; Maniecka and Polymenidou, 2015), in a similar way to the pathogenic prion protein, a concept known as the “prion-like mechanism” (Lee and Kim, 2015; Ayers and Cashman, 2018). In this model, misfolded proteins act as template seeds to trigger aggregation of their natively folded counterparts. This results in the propagation of protein misfolding, leading to its orderly spread through the CNS (Soto, 2012; Maniecka and Polymenidou, 2015). However, the question of where disease begins remains controversial because many researchers still favor the “dying-back” hypothesis, in which ALS begins within the muscle cells or at the NMJ. This hypothesis proposes that there is a spread of pathology from LMNs to UMNs (Chou and Norris, 1993; Fischer et al., 2004; Pun et al., 2006; Turner et al., 2018), or else, a simultaneous involvement of both UMNS and LMNs (Turner et al., 2018). Whilst most of the evidence for the dying-back mechanism comes from animal models, studies of muscle biopsies from early stage ALS patients and long-term survivors have demonstrated significant morphological abnormalities and major denervation/re-innervation at the NMJ, implying that this region is targeted early in disease (Millecamps et al., 2010; reviewed in Arbour et al., 2017).","tracks":[{"project":"2_test","denotations":[{"id":"31316328-24217521-38515585","span":{"begin":122,"end":126},"obj":"24217521"},{"id":"31316328-28710326-38515586","span":{"begin":142,"end":146},"obj":"28710326"},{"id":"31316328-23686809-38515587","span":{"begin":219,"end":223},"obj":"23686809"},{"id":"31316328-20308987-38515588","span":{"begin":449,"end":453},"obj":"20308987"},{"id":"31316328-25656065-38515589","span":{"begin":481,"end":485},"obj":"25656065"},{"id":"31316328-25792864-38515590","span":{"begin":598,"end":602},"obj":"25792864"},{"id":"31316328-29887144-38515591","span":{"begin":623,"end":627},"obj":"29887144"},{"id":"31316328-22632966-38515592","span":{"begin":856,"end":860},"obj":"22632966"},{"id":"31316328-25656065-38515593","span":{"begin":888,"end":892},"obj":"25656065"},{"id":"31316328-8332139-38515594","span":{"begin":1185,"end":1189},"obj":"8332139"},{"id":"31316328-14736504-38515595","span":{"begin":1207,"end":1211},"obj":"14736504"},{"id":"31316328-16474388-38515596","span":{"begin":1225,"end":1229},"obj":"16474388"},{"id":"31316328-29122933-38515597","span":{"begin":1246,"end":1250},"obj":"29122933"},{"id":"31316328-29122933-38515598","span":{"begin":1327,"end":1331},"obj":"29122933"},{"id":"31316328-20538972-38515599","span":{"begin":1680,"end":1684},"obj":"20538972"},{"id":"31316328-27633977-38515600","span":{"begin":1713,"end":1717},"obj":"27633977"}],"attributes":[{"subj":"31316328-24217521-38515585","pred":"source","obj":"2_test"},{"subj":"31316328-28710326-38515586","pred":"source","obj":"2_test"},{"subj":"31316328-23686809-38515587","pred":"source","obj":"2_test"},{"subj":"31316328-20308987-38515588","pred":"source","obj":"2_test"},{"subj":"31316328-25656065-38515589","pred":"source","obj":"2_test"},{"subj":"31316328-25792864-38515590","pred":"source","obj":"2_test"},{"subj":"31316328-29887144-38515591","pred":"source","obj":"2_test"},{"subj":"31316328-22632966-38515592","pred":"source","obj":"2_test"},{"subj":"31316328-25656065-38515593","pred":"source","obj":"2_test"},{"subj":"31316328-8332139-38515594","pred":"source","obj":"2_test"},{"subj":"31316328-14736504-38515595","pred":"source","obj":"2_test"},{"subj":"31316328-16474388-38515596","pred":"source","obj":"2_test"},{"subj":"31316328-29122933-38515597","pred":"source","obj":"2_test"},{"subj":"31316328-29122933-38515598","pred":"source","obj":"2_test"},{"subj":"31316328-20538972-38515599","pred":"source","obj":"2_test"},{"subj":"31316328-27633977-38515600","pred":"source","obj":"2_test"}]},{"project":"0_colil","denotations":[{"id":"31316328-24217521-631042","span":{"begin":122,"end":126},"obj":"24217521"},{"id":"31316328-28710326-631043","span":{"begin":142,"end":146},"obj":"28710326"},{"id":"31316328-23686809-631044","span":{"begin":219,"end":223},"obj":"23686809"},{"id":"31316328-20308987-631045","span":{"begin":449,"end":453},"obj":"20308987"},{"id":"31316328-25656065-631046","span":{"begin":481,"end":485},"obj":"25656065"},{"id":"31316328-25792864-631047","span":{"begin":598,"end":602},"obj":"25792864"},{"id":"31316328-29887144-631048","span":{"begin":623,"end":627},"obj":"29887144"},{"id":"31316328-22632966-631049","span":{"begin":856,"end":860},"obj":"22632966"},{"id":"31316328-25656065-631050","span":{"begin":888,"end":892},"obj":"25656065"},{"id":"31316328-8332139-631051","span":{"begin":1185,"end":1189},"obj":"8332139"},{"id":"31316328-14736504-631052","span":{"begin":1207,"end":1211},"obj":"14736504"},{"id":"31316328-16474388-631053","span":{"begin":1225,"end":1229},"obj":"16474388"},{"id":"31316328-29122933-631054","span":{"begin":1246,"end":1250},"obj":"29122933"},{"id":"31316328-29122933-631055","span":{"begin":1327,"end":1331},"obj":"29122933"},{"id":"31316328-20538972-631056","span":{"begin":1680,"end":1684},"obj":"20538972"},{"id":"31316328-27633977-631057","span":{"begin":1713,"end":1717},"obj":"27633977"}],"attributes":[{"subj":"31316328-24217521-631042","pred":"source","obj":"0_colil"},{"subj":"31316328-28710326-631043","pred":"source","obj":"0_colil"},{"subj":"31316328-23686809-631044","pred":"source","obj":"0_colil"},{"subj":"31316328-20308987-631045","pred":"source","obj":"0_colil"},{"subj":"31316328-25656065-631046","pred":"source","obj":"0_colil"},{"subj":"31316328-25792864-631047","pred":"source","obj":"0_colil"},{"subj":"31316328-29887144-631048","pred":"source","obj":"0_colil"},{"subj":"31316328-22632966-631049","pred":"source","obj":"0_colil"},{"subj":"31316328-25656065-631050","pred":"source","obj":"0_colil"},{"subj":"31316328-8332139-631051","pred":"source","obj":"0_colil"},{"subj":"31316328-14736504-631052","pred":"source","obj":"0_colil"},{"subj":"31316328-16474388-631053","pred":"source","obj":"0_colil"},{"subj":"31316328-29122933-631054","pred":"source","obj":"0_colil"},{"subj":"31316328-29122933-631055","pred":"source","obj":"0_colil"},{"subj":"31316328-20538972-631056","pred":"source","obj":"0_colil"},{"subj":"31316328-27633977-631057","pred":"source","obj":"0_colil"}]}],"confi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