PMC:6582309 / 32638-35742 JSONTXT

{"project":"2_test","denotations":[{"id":"31249505-27016693-38601644","span":{"begin":269,"end":273},"obj":"27016693"},{"id":"31249505-9019820-38601645","span":{"begin":439,"end":443},"obj":"9019820"},{"id":"31249505-21045163-38601646","span":{"begin":592,"end":596},"obj":"21045163"},{"id":"31249505-9019820-38601647","span":{"begin":690,"end":694},"obj":"9019820"},{"id":"31249505-30587772-38601648","span":{"begin":946,"end":950},"obj":"30587772"},{"id":"31249505-15181244-38601649","span":{"begin":1254,"end":1258},"obj":"15181244"},{"id":"31249505-23226438-38601650","span":{"begin":1274,"end":1278},"obj":"23226438"},{"id":"31249505-29379882-38601651","span":{"begin":1295,"end":1299},"obj":"29379882"},{"id":"31249505-10604434-38601652","span":{"begin":1493,"end":1497},"obj":"10604434"},{"id":"31249505-28483344-38601653","span":{"begin":1518,"end":1522},"obj":"28483344"},{"id":"31249505-1303239-38601654","span":{"begin":1617,"end":1621},"obj":"1303239"},{"id":"31249505-11409420-38601655","span":{"begin":1641,"end":1645},"obj":"11409420"},{"id":"31249505-15365148-38601656","span":{"begin":1661,"end":1665},"obj":"15365148"},{"id":"31249505-20697050-38601657","span":{"begin":1683,"end":1687},"obj":"20697050"},{"id":"31249505-27858710-38601658","span":{"begin":1704,"end":1708},"obj":"27858710"},{"id":"31249505-18184371-38601659","span":{"begin":1795,"end":1799},"obj":"18184371"},{"id":"31249505-23771217-38601660","span":{"begin":2067,"end":2071},"obj":"23771217"},{"id":"31249505-26341746-38601661","span":{"begin":2084,"end":2088},"obj":"26341746"},{"id":"31249505-26162235-38601662","span":{"begin":2493,"end":2497},"obj":"26162235"},{"id":"31249505-27838005-38601663","span":{"begin":2516,"end":2520},"obj":"27838005"},{"id":"31249505-8446170-38601664","span":{"begin":2653,"end":2657},"obj":"8446170"},{"id":"31249505-27185954-38601665","span":{"begin":2887,"end":2891},"obj":"27185954"}],"text":"Genetics\nThe incidence of human neurodegeneration and associated dementias is sporadic and is only rarely due to hereditary changes that are linked with genetic mutations. The majority of AD cases are sporadic late-onset (LOAD) with an unknown etiology (Cacace et al., 2016). The other rare AD form is genetically determined familial AD. Known specific gene mutations are the root cause for the development of familial form of AD (Selkoe, 1997). Most of the patients with early onset, familial form of AD have mutations in one of the two presenilin proteins (PSEN1 and PSEN2) (Bekris et al., 2010), which are proteins with a role in Aβ generation. Mutations also occur in APP gene (Selkoe, 1997). Polymorphism in APOEε4 allele of apolipoprotein E gene (APOE) is the major genetic risk factor for LOAD along with polymorphism in TREM2 gene, which has a role in maintaining normal immune functions in the brain (reviewed in detail in Wolfe et al., 2018). In population studies, several genetic loci have been identified as risk factors for AD (e.g., CLU, CR1, APP, PICALM, BIN1, ABCA7, MS4A, MEF2C CD33, EPHA1, CD2AP, APOE, TRIP4, TREM2, SORL1), although the connection between genes in these loci and pathogenesis of AD has not been established (Ashford, 2004; Karch et al., 2012; Mäkelä et al., 2018). Interestingly, the APOE4 polymorphism is unique to humans and its evolvement from the presumably ancestral primate form might have been instrumental for the AD pathogenesis (Mahley and Rall, 1999; Walker and Jucker, 2017).\nSome presenilin mutations and mutations in APP have been connected to CAA (Hendriks et al., 1992; Grabowski et al., 2001; Rossi et al., 2004; Bugiani et al., 2010; Sellal et al., 2017) and also a polymorphism in the neprilysin gene was associated with CAA (Kumar-Singh, 2008), although the exact connections between these mutations and AD/CAA symptoms and progression are not yet understood. Furthermore, APOEε4 was shown to be a risk factor for CAA and both APOEε2 and ε4 alleles are associated with more severe forms of CAA (Nelson et al., 2013; Yu et al., 2015).\nNo mutations in specific genes have been reported in dogs with CCD so far. The only neurodegenerative disease in dogs that has been linked to specific mutation is degenerative myelopathy (DM), a condition caused by both demyelination and axonal loss in the canine spinal cord. In dogs with this disease, mutations have been found in a gene SOD1, coding for superoxide dismutase enzyme (Nakamae et al., 2015; Kobatake et al., 2016). Interestingly, this gene is in human patients associated with some forms of familial amyotrophic lateral sclerosis (Rosen et al., 1993). Beside mutations in SOD1 gene, risk for developing DM in dogs, as well as onset of disease, seem to be partially modulated by gene encoding SP110 nuclear body protein (SP110) at least in Pembroke Welsh Corgis (Ivansson et al., 2016). No other mutations or disease modifying loci related to neurodegeneration have been detected in dogs so far and thus, little is known about the potential genetic risks or genetic predisposition for CCD and CAA."}

{"project":"0_colil","denotations":[{"id":"31249505-27016693-737069","span":{"begin":269,"end":273},"obj":"27016693"},{"id":"31249505-9019820-737070","span":{"begin":439,"end":443},"obj":"9019820"},{"id":"31249505-21045163-737071","span":{"begin":592,"end":596},"obj":"21045163"},{"id":"31249505-9019820-737072","span":{"begin":690,"end":694},"obj":"9019820"},{"id":"31249505-30587772-737073","span":{"begin":946,"end":950},"obj":"30587772"},{"id":"31249505-15181244-737074","span":{"begin":1254,"end":1258},"obj":"15181244"},{"id":"31249505-23226438-737075","span":{"begin":1274,"end":1278},"obj":"23226438"},{"id":"31249505-29379882-737076","span":{"begin":1295,"end":1299},"obj":"29379882"},{"id":"31249505-10604434-737077","span":{"begin":1493,"end":1497},"obj":"10604434"},{"id":"31249505-28483344-737078","span":{"begin":1518,"end":1522},"obj":"28483344"},{"id":"31249505-1303239-737079","span":{"begin":1617,"end":1621},"obj":"1303239"},{"id":"31249505-11409420-737080","span":{"begin":1641,"end":1645},"obj":"11409420"},{"id":"31249505-15365148-737081","span":{"begin":1661,"end":1665},"obj":"15365148"},{"id":"31249505-20697050-737082","span":{"begin":1683,"end":1687},"obj":"20697050"},{"id":"31249505-27858710-737083","span":{"begin":1704,"end":1708},"obj":"27858710"},{"id":"31249505-18184371-737084","span":{"begin":1795,"end":1799},"obj":"18184371"},{"id":"31249505-23771217-737085","span":{"begin":2067,"end":2071},"obj":"23771217"},{"id":"31249505-26341746-737086","span":{"begin":2084,"end":2088},"obj":"26341746"},{"id":"31249505-26162235-737087","span":{"begin":2493,"end":2497},"obj":"26162235"},{"id":"31249505-27838005-737088","span":{"begin":2516,"end":2520},"obj":"27838005"},{"id":"31249505-8446170-737089","span":{"begin":2653,"end":2657},"obj":"8446170"},{"id":"31249505-27185954-737090","span":{"begin":2887,"end":2891},"obj":"27185954"}],"text":"Genetics\nThe incidence of human neurodegeneration and associated dementias is sporadic and is only rarely due to hereditary changes that are linked with genetic mutations. The majority of AD cases are sporadic late-onset (LOAD) with an unknown etiology (Cacace et al., 2016). The other rare AD form is genetically determined familial AD. Known specific gene mutations are the root cause for the development of familial form of AD (Selkoe, 1997). Most of the patients with early onset, familial form of AD have mutations in one of the two presenilin proteins (PSEN1 and PSEN2) (Bekris et al., 2010), which are proteins with a role in Aβ generation. Mutations also occur in APP gene (Selkoe, 1997). Polymorphism in APOEε4 allele of apolipoprotein E gene (APOE) is the major genetic risk factor for LOAD along with polymorphism in TREM2 gene, which has a role in maintaining normal immune functions in the brain (reviewed in detail in Wolfe et al., 2018). In population studies, several genetic loci have been identified as risk factors for AD (e.g., CLU, CR1, APP, PICALM, BIN1, ABCA7, MS4A, MEF2C CD33, EPHA1, CD2AP, APOE, TRIP4, TREM2, SORL1), although the connection between genes in these loci and pathogenesis of AD has not been established (Ashford, 2004; Karch et al., 2012; Mäkelä et al., 2018). Interestingly, the APOE4 polymorphism is unique to humans and its evolvement from the presumably ancestral primate form might have been instrumental for the AD pathogenesis (Mahley and Rall, 1999; Walker and Jucker, 2017).\nSome presenilin mutations and mutations in APP have been connected to CAA (Hendriks et al., 1992; Grabowski et al., 2001; Rossi et al., 2004; Bugiani et al., 2010; Sellal et al., 2017) and also a polymorphism in the neprilysin gene was associated with CAA (Kumar-Singh, 2008), although the exact connections between these mutations and AD/CAA symptoms and progression are not yet understood. Furthermore, APOEε4 was shown to be a risk factor for CAA and both APOEε2 and ε4 alleles are associated with more severe forms of CAA (Nelson et al., 2013; Yu et al., 2015).\nNo mutations in specific genes have been reported in dogs with CCD so far. The only neurodegenerative disease in dogs that has been linked to specific mutation is degenerative myelopathy (DM), a condition caused by both demyelination and axonal loss in the canine spinal cord. In dogs with this disease, mutations have been found in a gene SOD1, coding for superoxide dismutase enzyme (Nakamae et al., 2015; Kobatake et al., 2016). Interestingly, this gene is in human patients associated with some forms of familial amyotrophic lateral sclerosis (Rosen et al., 1993). Beside mutations in SOD1 gene, risk for developing DM in dogs, as well as onset of disease, seem to be partially modulated by gene encoding SP110 nuclear body protein (SP110) at least in Pembroke Welsh Corgis (Ivansson et al., 2016). No other mutations or disease modifying loci related to neurodegeneration have been detected in dogs so far and thus, little is known about the potential genetic risks or genetic predisposition for CCD and CAA."}