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

Wouter Van Overbeke, 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, Jan Gettemans

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2492-2507
Number of pages16
JournalHuman Molecular Genetics
Volume24
Issue number9
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Fingerprint

Single-Domain Antibodies
Gelsolin
Amyloidosis
Amyloid
Furin
Proteolysis
Familial Amyloidosis
Genetic Hybridization
Matrix Metalloproteinase 14
trans-Golgi Network
Molecular Chaperones
Point Mutation
Genes
Peptide Hydrolases
Therapeutics
X-Rays
Genome
Calcium
Muscles
Peptides

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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

An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model. / Van Overbeke, Wouter; Wongsantichon, Jantana; Everaert, Inge; Verhelle, Adriaan; Zwaenepoel, Olivier; Loonchanta, Anantasak; Burtnick, Leslie D.; De Ganck, Ariane; Hochepied, Tino; Haigh, Jody; Cuvelier, Claude; Derave, Wim; Robinson, Robert C.; Gettemans, Jan.

In: Human Molecular Genetics, Vol. 24, No. 9, 01.01.2015, p. 2492-2507.

Research output: Contribution to journalArticle

Van Overbeke, W, Wongsantichon, J, Everaert, I, Verhelle, A, Zwaenepoel, O, Loonchanta, A, Burtnick, LD, De Ganck, A, Hochepied, T, Haigh, J, Cuvelier, C, Derave, W, Robinson, RC & Gettemans, J 2015, '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. https://doi.org/10.1093/hmg/ddv010
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 Jan 1;24(9):2492-2507. https://doi.org/10.1093/hmg/ddv010
Van Overbeke, Wouter ; Wongsantichon, Jantana ; Everaert, Inge ; Verhelle, Adriaan ; Zwaenepoel, Olivier ; Loonchanta, Anantasak ; Burtnick, Leslie D. ; De Ganck, Ariane ; Hochepied, Tino ; Haigh, Jody ; Cuvelier, Claude ; Derave, Wim ; Robinson, Robert C. ; Gettemans, Jan. / An ER-directed gelsolin nanobody targets the first step in amyloid formation in a gelsolin amyloidosis mouse model. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 9. pp. 2492-2507.
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