PMC:4621299 / 15423-21315 JSONTXT

{"project":"TEST0","denotations":[{"id":"26578865-196-204-323917","span":{"begin":428,"end":432},"obj":"[\"20798282\"]"},{"id":"26578865-221-229-323918","span":{"begin":453,"end":457},"obj":"[\"20392839\"]"},{"id":"26578865-127-135-323919","span":{"begin":828,"end":832},"obj":"[\"12589064\"]"},{"id":"26578865-133-141-323920","span":{"begin":834,"end":838},"obj":"[\"15331663\"]"},{"id":"26578865-214-222-323921","span":{"begin":1055,"end":1059},"obj":"[\"20392839\"]"},{"id":"26578865-128-136-323924","span":{"begin":1644,"end":1648},"obj":"[\"17389686\"]"},{"id":"26578865-195-203-323925","span":{"begin":1846,"end":1850},"obj":"[\"23212845\"]"},{"id":"26578865-229-237-323926","span":{"begin":2326,"end":2330},"obj":"[\"25556159\"]"},{"id":"26578865-235-243-323927","span":{"begin":2568,"end":2572},"obj":"[\"17015223\"]"},{"id":"26578865-228-236-323928","span":{"begin":2588,"end":2592},"obj":"[\"21725313\"]"},{"id":"26578865-232-240-323929","span":{"begin":2614,"end":2618},"obj":"[\"22315713\"]"},{"id":"26578865-187-195-323931","span":{"begin":3376,"end":3380},"obj":"[\"25596448\"]"},{"id":"26578865-230-238-323932","span":{"begin":3853,"end":3857},"obj":"[\"21549339\"]"},{"id":"26578865-103-111-323933","span":{"begin":3972,"end":3976},"obj":"[\"8636227\"]"},{"id":"26578865-129-137-323934","span":{"begin":3998,"end":4002},"obj":"[\"8638159\"]"},{"id":"26578865-228-236-323935","span":{"begin":4097,"end":4101},"obj":"[\"11323436\"]"},{"id":"26578865-234-242-323936","span":{"begin":4119,"end":4123},"obj":"[\"11959998\"]"},{"id":"26578865-228-236-323937","span":{"begin":4136,"end":4140},"obj":"[\"12388752\"]"},{"id":"26578865-230-238-323938","span":{"begin":4158,"end":4162},"obj":"[\"20450495\"]"},{"id":"26578865-106-114-323939","span":{"begin":4271,"end":4275},"obj":"[\"25261468\"]"},{"id":"26578865-118-126-323940","span":{"begin":4613,"end":4617},"obj":"[\"9199167\"]"},{"id":"26578865-141-149-323941","span":{"begin":4636,"end":4640},"obj":"[\"9398683\"]"},{"id":"26578865-162-170-323942","span":{"begin":4657,"end":4661},"obj":"[\"24902738\"]"},{"id":"26578865-141-149-323943","span":{"begin":4805,"end":4809},"obj":"[\"21262811\"]"},{"id":"26578865-231-239-323944","span":{"begin":5189,"end":5193},"obj":"[\"24902738\"]"},{"id":"26578865-94-102-323945","span":{"begin":5290,"end":5294},"obj":"[\"17852734\"]"},{"id":"26578865-117-125-323946","span":{"begin":5313,"end":5317},"obj":"[\"18406529\"]"},{"id":"26578865-185-193-323947","span":{"begin":5505,"end":5509},"obj":"[\"15968592\"]"},{"id":"26578865-211-219-323948","span":{"begin":5531,"end":5535},"obj":"[\"21073448\"]"},{"id":"26578865-127-135-323949","span":{"begin":5665,"end":5669},"obj":"[\"9852078\"]"},{"id":"26578865-132-140-323950","span":{"begin":5804,"end":5808},"obj":"[\"15890653\"]"},{"id":"26578865-214-222-323951","span":{"begin":5886,"end":5890},"obj":"[\"19170188\"]"}],"text":"SNAREs\nGenetic deficiency in SNAREs was shown to be associated with the progression of neurodegenerative diseases like AD and PD. PD is marked by the presence of Lewy bodies which are principally composed of aggregated α-synuclein. Under physiological conditions, α-synuclein may regulate vesicle trafficking and promote synaptic transmission by binding directly to SNAREs and stimulating SNARE complex formation (Burré et al., 2010; Thayanidhi et al., 2010). Overexpression of wild type or the PD-associated mutant of α-synuclein (A53T) leads to cytotoxicity and inhibition of ER-to-Golgi trafficking in in vitro models which can be partially suppressed by co-overexpression of SNAREs Ykt6 or Sec22. Ykt6—a protein enriched in neurons—was more protective than Sec22 and suggests a specialized role in mammals (Hasegawa et al., 2003, 2004). In vitro binding experiments also point toward the direct interaction of α-synuclein with STX5 and GS27 along with mutant α-synuclein which destabilizes the STX5-GS27-rbet1-sec22b SNARE complex (Thayanidhi et al., 2010). This line of evidence further implicates trafficking defects in bringing about neurodegenerative cytotoxicity.\nAlthough the exact molecular mechanisms connecting Golgi fragmentation and disease mutations is still much under investigation, in vitro models can be used to recapitulate Golgi fragmentation seen in neurodegenerative disorders (Suga et al., 2005a). Fragmentation has been recreated in vitro and can be rescued by regulating levels of SNAREs. A STX5 knockdown is known to induce Golgi fragmentation in HeLa cells and cultured neurons (Suga et al., 2005a; Amessou et al., 2007). On the other hand, in PC12 cells treated with 6-hydroxydopamine or methamphetamine (an established in vitro PD model), a decrease in the level of STX5 rescues Golgi fragmentation (Rendón et al., 2013). This same study also demonstrated that Golgi fragmentation could intensify disease progression by inducing α-synuclein aggregation and the formation of Lewy bodies.\nSTX5 defects have also been shown to affect processing of AD-related proteins. In AD, amyloid precursor protein (APP) undergoes a series of proteolytic events by β- and γ-secretases to create the amyloidogenic variants of β-amyloid (Aβ) that are longer and more likely to form aggregates (Peric and Annaert, 2015). Presenilins form a complex with γ-secretase, and mutations in presenilin 1 (PS1) are the most frequently associated mutations found in AD which result in increased production of Aβ, or altered ratios of amyloid peptide species (Hardy, 2006; Saito et al., 2011; De Strooper et al., 2012). Overexpressed STX5 was shown to co-localize with and directly bind to PS1. Further, STX5 overexpression increased the accumulation of APP in the ER and cis-Golgi and inhibited Aβ secretion in a neuroblastoma cell line (NG108-15)(Suga et al., 2005b). In NG108-15 cells expressing the familial AD mutation PS1ΔE9, STX5 was shown to have a decreased association with presenilin. A study of ER stress in an AD model demonstrated that ER stressors can increase synthesis of STX5 and its accumulation in the ER-Golgi intermediate compartment (ERGIC) and transport vesicles. Thus, upregulation of trafficking machinery induced by ER stress could be a cellular mechanism for correcting the accumulation of the amyloidogenic cleavage products of APP (Suga et al., 2015).\nAs stated above, the cis-Golgi SNARE GS27 (GOSR2) binds to α-synuclein and is part of a SNARE complex that is destabilized by mutant α-synuclein. GS27 has also been shown to be associated with a neurological disorder in humans. Six patient were identified baring a mutation that results in improper subcellular localization and loss of function of GS27 leading to symptoms common in COG-CDG patients such as cerebral atrophy, epilepsy, and early ataxia (Corbett et al., 2011; Table 1).\nGS28 (GOSR1) is a Golgi SNARE involved in both ER-to-Golgi and intra-Golgi transport (Nagahama et al., 1996; Subramaniam et al., 1996), and accordingly has been shown to be associated with three SNARE complexes (Zhang and Hong, 2001; Parlati et al., 2002; Xu et al., 2002; Siddiqi et al., 2010). GS28 mutants have been used to study retinal degeneration in Drosophila photoreceptors (Rosenbaum et al., 2014). Lack of expression of GS28 in mutant flies alters trafficking and glycosylation of rhodopsin (Rh1). The photoreceptors in these mutants also exhibit enlarged ER and Golgi membranes and retinal degeneration over time.\nVti1a is a TGN-localized SNARE that functions in vesicle generation and Ca2+ channel trafficking (von Mollard et al., 1997; Lupashin et al., 1997; Walter et al., 2014). A double knockout of Vti1a and Vti1b genes results in progressive neurodegeneration and perinatal lethality in a mouse model (Kunwar et al., 2011). Single knockout of Vti1a or Vti1b does not result in a lethal phenotype indicating overlapping functions of these proteins. The death-after-birth clearly demonstrates that these SNAREs are not required during organismal development, indicating a specialized requirement for Vti1a and Vti1b in neurons leading to neurodegeneration in the double-knockout animals (Walter et al., 2014). Vti1a SNARE partners, STX6 and STX16, are also required for neurite outgrowth (Chua and Tang, 2008; Kabayama et al., 2008).\nIn humans, a disease known as CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome has been linked with loss of function mutations in SNAP29 (Sprecher et al., 2005; Fuchs-Telem et al., 2011). SNAP29 is a member of the SNAP25 family that localizes to the Golgi, endosomal, and lysosomal compartments (Steegmaier et al., 1998). CEDNIK patients exhibit severe neuropathy likely due to the loss of SNAP29 functional involvement in neurotransmission (Pan et al., 2005) and trafficking within neuroglia during active myelination (Schardt et al., 2009)."}

{"project":"0_colil","denotations":[{"id":"26578865-20798282-323917","span":{"begin":428,"end":432},"obj":"20798282"},{"id":"26578865-20392839-323918","span":{"begin":453,"end":457},"obj":"20392839"},{"id":"26578865-12589064-323919","span":{"begin":828,"end":832},"obj":"12589064"},{"id":"26578865-15331663-323920","span":{"begin":834,"end":838},"obj":"15331663"},{"id":"26578865-20392839-323921","span":{"begin":1055,"end":1059},"obj":"20392839"},{"id":"26578865-17389686-323924","span":{"begin":1644,"end":1648},"obj":"17389686"},{"id":"26578865-23212845-323925","span":{"begin":1846,"end":1850},"obj":"23212845"},{"id":"26578865-25556159-323926","span":{"begin":2326,"end":2330},"obj":"25556159"},{"id":"26578865-17015223-323927","span":{"begin":2568,"end":2572},"obj":"17015223"},{"id":"26578865-21725313-323928","span":{"begin":2588,"end":2592},"obj":"21725313"},{"id":"26578865-22315713-323929","span":{"begin":2614,"end":2618},"obj":"22315713"},{"id":"26578865-25596448-323931","span":{"begin":3376,"end":3380},"obj":"25596448"},{"id":"26578865-21549339-323932","span":{"begin":3853,"end":3857},"obj":"21549339"},{"id":"26578865-8636227-323933","span":{"begin":3972,"end":3976},"obj":"8636227"},{"id":"26578865-8638159-323934","span":{"begin":3998,"end":4002},"obj":"8638159"},{"id":"26578865-11323436-323935","span":{"begin":4097,"end":4101},"obj":"11323436"},{"id":"26578865-11959998-323936","span":{"begin":4119,"end":4123},"obj":"11959998"},{"id":"26578865-12388752-323937","span":{"begin":4136,"end":4140},"obj":"12388752"},{"id":"26578865-20450495-323938","span":{"begin":4158,"end":4162},"obj":"20450495"},{"id":"26578865-25261468-323939","span":{"begin":4271,"end":4275},"obj":"25261468"},{"id":"26578865-9199167-323940","span":{"begin":4613,"end":4617},"obj":"9199167"},{"id":"26578865-9398683-323941","span":{"begin":4636,"end":4640},"obj":"9398683"},{"id":"26578865-24902738-323942","span":{"begin":4657,"end":4661},"obj":"24902738"},{"id":"26578865-21262811-323943","span":{"begin":4805,"end":4809},"obj":"21262811"},{"id":"26578865-24902738-323944","span":{"begin":5189,"end":5193},"obj":"24902738"},{"id":"26578865-17852734-323945","span":{"begin":5290,"end":5294},"obj":"17852734"},{"id":"26578865-18406529-323946","span":{"begin":5313,"end":5317},"obj":"18406529"},{"id":"26578865-15968592-323947","span":{"begin":5505,"end":5509},"obj":"15968592"},{"id":"26578865-21073448-323948","span":{"begin":5531,"end":5535},"obj":"21073448"},{"id":"26578865-9852078-323949","span":{"begin":5665,"end":5669},"obj":"9852078"},{"id":"26578865-15890653-323950","span":{"begin":5804,"end":5808},"obj":"15890653"},{"id":"26578865-19170188-323951","span":{"begin":5886,"end":5890},"obj":"19170188"}],"text":"SNAREs\nGenetic deficiency in SNAREs was shown to be associated with the progression of neurodegenerative diseases like AD and PD. PD is marked by the presence of Lewy bodies which are principally composed of aggregated α-synuclein. Under physiological conditions, α-synuclein may regulate vesicle trafficking and promote synaptic transmission by binding directly to SNAREs and stimulating SNARE complex formation (Burré et al., 2010; Thayanidhi et al., 2010). Overexpression of wild type or the PD-associated mutant of α-synuclein (A53T) leads to cytotoxicity and inhibition of ER-to-Golgi trafficking in in vitro models which can be partially suppressed by co-overexpression of SNAREs Ykt6 or Sec22. Ykt6—a protein enriched in neurons—was more protective than Sec22 and suggests a specialized role in mammals (Hasegawa et al., 2003, 2004). In vitro binding experiments also point toward the direct interaction of α-synuclein with STX5 and GS27 along with mutant α-synuclein which destabilizes the STX5-GS27-rbet1-sec22b SNARE complex (Thayanidhi et al., 2010). This line of evidence further implicates trafficking defects in bringing about neurodegenerative cytotoxicity.\nAlthough the exact molecular mechanisms connecting Golgi fragmentation and disease mutations is still much under investigation, in vitro models can be used to recapitulate Golgi fragmentation seen in neurodegenerative disorders (Suga et al., 2005a). Fragmentation has been recreated in vitro and can be rescued by regulating levels of SNAREs. A STX5 knockdown is known to induce Golgi fragmentation in HeLa cells and cultured neurons (Suga et al., 2005a; Amessou et al., 2007). On the other hand, in PC12 cells treated with 6-hydroxydopamine or methamphetamine (an established in vitro PD model), a decrease in the level of STX5 rescues Golgi fragmentation (Rendón et al., 2013). This same study also demonstrated that Golgi fragmentation could intensify disease progression by inducing α-synuclein aggregation and the formation of Lewy bodies.\nSTX5 defects have also been shown to affect processing of AD-related proteins. In AD, amyloid precursor protein (APP) undergoes a series of proteolytic events by β- and γ-secretases to create the amyloidogenic variants of β-amyloid (Aβ) that are longer and more likely to form aggregates (Peric and Annaert, 2015). Presenilins form a complex with γ-secretase, and mutations in presenilin 1 (PS1) are the most frequently associated mutations found in AD which result in increased production of Aβ, or altered ratios of amyloid peptide species (Hardy, 2006; Saito et al., 2011; De Strooper et al., 2012). Overexpressed STX5 was shown to co-localize with and directly bind to PS1. Further, STX5 overexpression increased the accumulation of APP in the ER and cis-Golgi and inhibited Aβ secretion in a neuroblastoma cell line (NG108-15)(Suga et al., 2005b). In NG108-15 cells expressing the familial AD mutation PS1ΔE9, STX5 was shown to have a decreased association with presenilin. A study of ER stress in an AD model demonstrated that ER stressors can increase synthesis of STX5 and its accumulation in the ER-Golgi intermediate compartment (ERGIC) and transport vesicles. Thus, upregulation of trafficking machinery induced by ER stress could be a cellular mechanism for correcting the accumulation of the amyloidogenic cleavage products of APP (Suga et al., 2015).\nAs stated above, the cis-Golgi SNARE GS27 (GOSR2) binds to α-synuclein and is part of a SNARE complex that is destabilized by mutant α-synuclein. GS27 has also been shown to be associated with a neurological disorder in humans. Six patient were identified baring a mutation that results in improper subcellular localization and loss of function of GS27 leading to symptoms common in COG-CDG patients such as cerebral atrophy, epilepsy, and early ataxia (Corbett et al., 2011; Table 1).\nGS28 (GOSR1) is a Golgi SNARE involved in both ER-to-Golgi and intra-Golgi transport (Nagahama et al., 1996; Subramaniam et al., 1996), and accordingly has been shown to be associated with three SNARE complexes (Zhang and Hong, 2001; Parlati et al., 2002; Xu et al., 2002; Siddiqi et al., 2010). GS28 mutants have been used to study retinal degeneration in Drosophila photoreceptors (Rosenbaum et al., 2014). Lack of expression of GS28 in mutant flies alters trafficking and glycosylation of rhodopsin (Rh1). The photoreceptors in these mutants also exhibit enlarged ER and Golgi membranes and retinal degeneration over time.\nVti1a is a TGN-localized SNARE that functions in vesicle generation and Ca2+ channel trafficking (von Mollard et al., 1997; Lupashin et al., 1997; Walter et al., 2014). A double knockout of Vti1a and Vti1b genes results in progressive neurodegeneration and perinatal lethality in a mouse model (Kunwar et al., 2011). Single knockout of Vti1a or Vti1b does not result in a lethal phenotype indicating overlapping functions of these proteins. The death-after-birth clearly demonstrates that these SNAREs are not required during organismal development, indicating a specialized requirement for Vti1a and Vti1b in neurons leading to neurodegeneration in the double-knockout animals (Walter et al., 2014). Vti1a SNARE partners, STX6 and STX16, are also required for neurite outgrowth (Chua and Tang, 2008; Kabayama et al., 2008).\nIn humans, a disease known as CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome has been linked with loss of function mutations in SNAP29 (Sprecher et al., 2005; Fuchs-Telem et al., 2011). SNAP29 is a member of the SNAP25 family that localizes to the Golgi, endosomal, and lysosomal compartments (Steegmaier et al., 1998). CEDNIK patients exhibit severe neuropathy likely due to the loss of SNAP29 functional involvement in neurotransmission (Pan et al., 2005) and trafficking within neuroglia during active myelination (Schardt et al., 2009)."}

{"project":"2_test","denotations":[{"id":"26578865-20798282-38257398","span":{"begin":428,"end":432},"obj":"20798282"},{"id":"26578865-20392839-38257399","span":{"begin":453,"end":457},"obj":"20392839"},{"id":"26578865-12589064-38257400","span":{"begin":828,"end":832},"obj":"12589064"},{"id":"26578865-15331663-38257401","span":{"begin":834,"end":838},"obj":"15331663"},{"id":"26578865-20392839-38257402","span":{"begin":1055,"end":1059},"obj":"20392839"},{"id":"26578865-17389686-38257405","span":{"begin":1644,"end":1648},"obj":"17389686"},{"id":"26578865-23212845-38257406","span":{"begin":1846,"end":1850},"obj":"23212845"},{"id":"26578865-25556159-38257407","span":{"begin":2326,"end":2330},"obj":"25556159"},{"id":"26578865-17015223-38257408","span":{"begin":2568,"end":2572},"obj":"17015223"},{"id":"26578865-21725313-38257409","span":{"begin":2588,"end":2592},"obj":"21725313"},{"id":"26578865-22315713-38257410","span":{"begin":2614,"end":2618},"obj":"22315713"},{"id":"26578865-25596448-38257412","span":{"begin":3376,"end":3380},"obj":"25596448"},{"id":"26578865-21549339-38257413","span":{"begin":3853,"end":3857},"obj":"21549339"},{"id":"26578865-8636227-38257414","span":{"begin":3972,"end":3976},"obj":"8636227"},{"id":"26578865-8638159-38257415","span":{"begin":3998,"end":4002},"obj":"8638159"},{"id":"26578865-11323436-38257416","span":{"begin":4097,"end":4101},"obj":"11323436"},{"id":"26578865-11959998-38257417","span":{"begin":4119,"end":4123},"obj":"11959998"},{"id":"26578865-12388752-38257418","span":{"begin":4136,"end":4140},"obj":"12388752"},{"id":"26578865-20450495-38257419","span":{"begin":4158,"end":4162},"obj":"20450495"},{"id":"26578865-25261468-38257420","span":{"begin":4271,"end":4275},"obj":"25261468"},{"id":"26578865-9199167-38257421","span":{"begin":4613,"end":4617},"obj":"9199167"},{"id":"26578865-9398683-38257422","span":{"begin":4636,"end":4640},"obj":"9398683"},{"id":"26578865-24902738-38257423","span":{"begin":4657,"end":4661},"obj":"24902738"},{"id":"26578865-21262811-38257424","span":{"begin":4805,"end":4809},"obj":"21262811"},{"id":"26578865-24902738-38257425","span":{"begin":5189,"end":5193},"obj":"24902738"},{"id":"26578865-17852734-38257426","span":{"begin":5290,"end":5294},"obj":"17852734"},{"id":"26578865-18406529-38257427","span":{"begin":5313,"end":5317},"obj":"18406529"},{"id":"26578865-15968592-38257428","span":{"begin":5505,"end":5509},"obj":"15968592"},{"id":"26578865-21073448-38257429","span":{"begin":5531,"end":5535},"obj":"21073448"},{"id":"26578865-9852078-38257430","span":{"begin":5665,"end":5669},"obj":"9852078"},{"id":"26578865-15890653-38257431","span":{"begin":5804,"end":5808},"obj":"15890653"},{"id":"26578865-19170188-38257432","span":{"begin":5886,"end":5890},"obj":"19170188"}],"text":"SNAREs\nGenetic deficiency in SNAREs was shown to be associated with the progression of neurodegenerative diseases like AD and PD. PD is marked by the presence of Lewy bodies which are principally composed of aggregated α-synuclein. Under physiological conditions, α-synuclein may regulate vesicle trafficking and promote synaptic transmission by binding directly to SNAREs and stimulating SNARE complex formation (Burré et al., 2010; Thayanidhi et al., 2010). Overexpression of wild type or the PD-associated mutant of α-synuclein (A53T) leads to cytotoxicity and inhibition of ER-to-Golgi trafficking in in vitro models which can be partially suppressed by co-overexpression of SNAREs Ykt6 or Sec22. Ykt6—a protein enriched in neurons—was more protective than Sec22 and suggests a specialized role in mammals (Hasegawa et al., 2003, 2004). In vitro binding experiments also point toward the direct interaction of α-synuclein with STX5 and GS27 along with mutant α-synuclein which destabilizes the STX5-GS27-rbet1-sec22b SNARE complex (Thayanidhi et al., 2010). This line of evidence further implicates trafficking defects in bringing about neurodegenerative cytotoxicity.\nAlthough the exact molecular mechanisms connecting Golgi fragmentation and disease mutations is still much under investigation, in vitro models can be used to recapitulate Golgi fragmentation seen in neurodegenerative disorders (Suga et al., 2005a). Fragmentation has been recreated in vitro and can be rescued by regulating levels of SNAREs. A STX5 knockdown is known to induce Golgi fragmentation in HeLa cells and cultured neurons (Suga et al., 2005a; Amessou et al., 2007). On the other hand, in PC12 cells treated with 6-hydroxydopamine or methamphetamine (an established in vitro PD model), a decrease in the level of STX5 rescues Golgi fragmentation (Rendón et al., 2013). This same study also demonstrated that Golgi fragmentation could intensify disease progression by inducing α-synuclein aggregation and the formation of Lewy bodies.\nSTX5 defects have also been shown to affect processing of AD-related proteins. In AD, amyloid precursor protein (APP) undergoes a series of proteolytic events by β- and γ-secretases to create the amyloidogenic variants of β-amyloid (Aβ) that are longer and more likely to form aggregates (Peric and Annaert, 2015). Presenilins form a complex with γ-secretase, and mutations in presenilin 1 (PS1) are the most frequently associated mutations found in AD which result in increased production of Aβ, or altered ratios of amyloid peptide species (Hardy, 2006; Saito et al., 2011; De Strooper et al., 2012). Overexpressed STX5 was shown to co-localize with and directly bind to PS1. Further, STX5 overexpression increased the accumulation of APP in the ER and cis-Golgi and inhibited Aβ secretion in a neuroblastoma cell line (NG108-15)(Suga et al., 2005b). In NG108-15 cells expressing the familial AD mutation PS1ΔE9, STX5 was shown to have a decreased association with presenilin. A study of ER stress in an AD model demonstrated that ER stressors can increase synthesis of STX5 and its accumulation in the ER-Golgi intermediate compartment (ERGIC) and transport vesicles. Thus, upregulation of trafficking machinery induced by ER stress could be a cellular mechanism for correcting the accumulation of the amyloidogenic cleavage products of APP (Suga et al., 2015).\nAs stated above, the cis-Golgi SNARE GS27 (GOSR2) binds to α-synuclein and is part of a SNARE complex that is destabilized by mutant α-synuclein. GS27 has also been shown to be associated with a neurological disorder in humans. Six patient were identified baring a mutation that results in improper subcellular localization and loss of function of GS27 leading to symptoms common in COG-CDG patients such as cerebral atrophy, epilepsy, and early ataxia (Corbett et al., 2011; Table 1).\nGS28 (GOSR1) is a Golgi SNARE involved in both ER-to-Golgi and intra-Golgi transport (Nagahama et al., 1996; Subramaniam et al., 1996), and accordingly has been shown to be associated with three SNARE complexes (Zhang and Hong, 2001; Parlati et al., 2002; Xu et al., 2002; Siddiqi et al., 2010). GS28 mutants have been used to study retinal degeneration in Drosophila photoreceptors (Rosenbaum et al., 2014). Lack of expression of GS28 in mutant flies alters trafficking and glycosylation of rhodopsin (Rh1). The photoreceptors in these mutants also exhibit enlarged ER and Golgi membranes and retinal degeneration over time.\nVti1a is a TGN-localized SNARE that functions in vesicle generation and Ca2+ channel trafficking (von Mollard et al., 1997; Lupashin et al., 1997; Walter et al., 2014). A double knockout of Vti1a and Vti1b genes results in progressive neurodegeneration and perinatal lethality in a mouse model (Kunwar et al., 2011). Single knockout of Vti1a or Vti1b does not result in a lethal phenotype indicating overlapping functions of these proteins. The death-after-birth clearly demonstrates that these SNAREs are not required during organismal development, indicating a specialized requirement for Vti1a and Vti1b in neurons leading to neurodegeneration in the double-knockout animals (Walter et al., 2014). Vti1a SNARE partners, STX6 and STX16, are also required for neurite outgrowth (Chua and Tang, 2008; Kabayama et al., 2008).\nIn humans, a disease known as CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome has been linked with loss of function mutations in SNAP29 (Sprecher et al., 2005; Fuchs-Telem et al., 2011). SNAP29 is a member of the SNAP25 family that localizes to the Golgi, endosomal, and lysosomal compartments (Steegmaier et al., 1998). CEDNIK patients exhibit severe neuropathy likely due to the loss of SNAP29 functional involvement in neurotransmission (Pan et al., 2005) and trafficking within neuroglia during active myelination (Schardt et al., 2009)."}