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An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model

Wouter Van Overbeke (UGent) , Jantana Wongsantichon, Inge Everaert (UGent) , Adriaan Verhelle (UGent) , Olivier Zwaenepoel (UGent) , Anantasak Loonchanta, Leslie D Burtnick, Ariane De Ganck (UGent) , Tino Hochepied (UGent) , Jody Haigh (UGent) , et al.
(2015) HUMAN MOLECULAR GENETICS. 24(9). p.2492-2507
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Abstract
Hereditary gelsolin amyloidosis is an autosomal dominantly inherited amyloid disorder. A point mutation in the GSN gene (G654A being the most common one) results in disturbed calcium binding by the second gelsolin domain (G2). As a result, the folding of G2 is hampered, rendering the mutant plasma gelsolin susceptible to a proteolytic cascade. Consecutive cleavage by furin and MT1-MMP-like proteases generates 8 and 5 kDa amyloidogenic peptides that cause neurological, ophthalmological and dermatological findings. To this day, no specific treatment is available to counter the pathogenesis. Using GSN nanobody 11 as a molecular chaperone, we aimed to protect mutant plasma gelsolin from furin proteolysis in the trans-Golgi network. We report a transgenic, GSN nanobody 11 secreting mouse that was used for crossbreeding with gelsolin amyloidosis mice. Insertion of the therapeutic nanobody gene into the gelsolin amyloidosis mouse genome resulted in improved muscle contractility. X-ray crystal structure determination of the gelsolin G2:Nb11 complex revealed that Nb11 does not directly block the furin cleavage site. We conclude that nanobodies can be used to shield substrates from aberrant proteolysis and this approach might establish a novel therapeutic strategy in amyloid diseases.
Keywords
FAMILIAL AMYLOIDOSIS, BETA-PROTEIN FIBRILLOGENESIS, FINNISH TYPE, PLASMA GELSOLIN, PROPROTEIN CONVERTASE, IN-VITRO, DOMAIN 2, FURIN, ACTIN, CELLS

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MLA
Van Overbeke, Wouter, et al. “An ER-Directed Gelsolin Nanobody Targets the First Step in Amyloid Formation in a Gelsolin Amyloidosis Mouse Model.” HUMAN MOLECULAR GENETICS, vol. 24, no. 9, 2015, pp. 2492–507, doi:10.1093/hmg/ddv010.
APA
Van Overbeke, W., Wongsantichon, J., Everaert, I., Verhelle, A., Zwaenepoel, O., Loonchanta, A., … Gettemans, J. (2015). An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model. HUMAN MOLECULAR GENETICS, 24(9), 2492–2507. https://doi.org/10.1093/hmg/ddv010
Chicago author-date
Van Overbeke, Wouter, Jantana Wongsantichon, Inge Everaert, Adriaan Verhelle, Olivier Zwaenepoel, Anantasak Loonchanta, Leslie D Burtnick, et al. 2015. “An ER-Directed Gelsolin Nanobody Targets the First Step in Amyloid Formation in a Gelsolin Amyloidosis Mouse Model.” HUMAN MOLECULAR GENETICS 24 (9): 2492–2507. https://doi.org/10.1093/hmg/ddv010.
Chicago author-date (all authors)
Van Overbeke, Wouter, Jantana Wongsantichon, Inge Everaert, Adriaan Verhelle, Olivier Zwaenepoel, Anantasak Loonchanta, Leslie D Burtnick, Ariane De Ganck, Tino Hochepied, Jody Haigh, Claude Cuvelier, Wim Derave, Robert C Robinson, and Jan Gettemans. 2015. “An ER-Directed Gelsolin Nanobody Targets the First Step in Amyloid Formation in a Gelsolin Amyloidosis Mouse Model.” HUMAN MOLECULAR GENETICS 24 (9): 2492–2507. doi:10.1093/hmg/ddv010.
Vancouver
1.
Van Overbeke W, Wongsantichon J, Everaert I, Verhelle A, Zwaenepoel O, Loonchanta A, et al. An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model. HUMAN MOLECULAR GENETICS. 2015;24(9):2492–507.
IEEE
[1]
W. Van Overbeke et al., “An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model,” HUMAN MOLECULAR GENETICS, vol. 24, no. 9, pp. 2492–2507, 2015.
@article{5865329,
  abstract     = {{Hereditary gelsolin amyloidosis is an autosomal dominantly inherited amyloid disorder. A point mutation in the GSN gene (G654A being the most common one) results in disturbed calcium binding by the second gelsolin domain (G2). As a result, the folding of G2 is hampered, rendering the mutant plasma gelsolin susceptible to a proteolytic cascade. Consecutive cleavage by furin and MT1-MMP-like proteases generates 8 and 5 kDa amyloidogenic peptides that cause neurological, ophthalmological and dermatological findings. To this day, no specific treatment is available to counter the pathogenesis. Using GSN nanobody 11 as a molecular chaperone, we aimed to protect mutant plasma gelsolin from furin proteolysis in the trans-Golgi network. We report a transgenic, GSN nanobody 11 secreting mouse that was used for crossbreeding with gelsolin amyloidosis mice. Insertion of the therapeutic nanobody gene into the gelsolin amyloidosis mouse genome resulted in improved muscle contractility. X-ray crystal structure determination of the gelsolin G2:Nb11 complex revealed that Nb11 does not directly block the furin cleavage site. We conclude that nanobodies can be used to shield substrates from aberrant proteolysis and this approach might establish a novel therapeutic strategy in amyloid diseases.}},
  author       = {{Van Overbeke, Wouter and Wongsantichon, Jantana and Everaert, Inge and Verhelle, Adriaan and Zwaenepoel, Olivier and Loonchanta, Anantasak and Burtnick, Leslie D and De Ganck, Ariane and Hochepied, Tino and Haigh, Jody and Cuvelier, Claude and Derave, Wim and Robinson, Robert C and Gettemans, Jan}},
  issn         = {{0964-6906}},
  journal      = {{HUMAN MOLECULAR GENETICS}},
  keywords     = {{FAMILIAL AMYLOIDOSIS,BETA-PROTEIN FIBRILLOGENESIS,FINNISH TYPE,PLASMA GELSOLIN,PROPROTEIN CONVERTASE,IN-VITRO,DOMAIN 2,FURIN,ACTIN,CELLS}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2492--2507}},
  title        = {{An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model}},
  url          = {{http://doi.org/10.1093/hmg/ddv010}},
  volume       = {{24}},
  year         = {{2015}},
}
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