Dataset Information

Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model.

ABSTRACT: Gelsolin amyloidosis is an autosomal dominant incurable disease caused by a point mutation in the GSN gene (G654A/T), specifically affecting secreted plasma gelsolin. Incorrect folding of the mutant (D187N/Y) second gelsolin domain leads to a pathological proteolytic cascade. D187N/Y gelsolin is first cleaved by furin in the trans-Golgi network, generating a 68?kDa fragment (C68). Upon secretion, C68 is cleaved by MT1-MMP-like proteases in the extracellular matrix, releasing 8?kDa and 5?kDa amyloidogenic peptides which aggregate in multiple tissues and cause disease-associated symptoms. We developed nanobodies that recognize the C68 fragment, but not native wild type gelsolin, and used these as molecular chaperones to mitigate gelsolin amyloid buildup in a mouse model that recapitulates the proteolytic cascade. We identified gelsolin nanobodies that potently reduce C68 proteolysis by MT1-MMP in vitro. Converting these nanobodies into an albumin-binding format drastically increased their serum half-life in mice, rendering them suitable for intraperitoneal injection. A 12-week treatment schedule of heterozygote D187N gelsolin transgenic mice with recombinant bispecific gelsolin-albumin nanobody significantly decreased gelsolin buildup in the endomysium and concomitantly improved muscle contractile properties. These findings demonstrate that nanobodies may be of considerable value in the treatment of gelsolin amyloidosis and related diseases.

SUBMITTER: Van Overbeke W

PROVIDER: S-EPMC4428403 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model.

Van Overbeke Wouter W Verhelle Adriaan A Everaert Inge I Zwaenepoel Olivier O Vandekerckhove Joël J Cuvelier Claude C Derave Wim W Gettemans Jan J

Molecular therapy : the journal of the American Society of Gene Therapy 20140715 10

Gelsolin amyloidosis is an autosomal dominant incurable disease caused by a point mutation in the GSN gene (G654A/T), specifically affecting secreted plasma gelsolin. Incorrect folding of the mutant (D187N/Y) second gelsolin domain leads to a pathological proteolytic cascade. D187N/Y gelsolin is first cleaved by furin in the trans-Golgi network, generating a 68 kDa fragment (C68). Upon secretion, C68 is cleaved by MT1-MMP-like proteases in the extracellular matrix, releasing 8 kDa and 5 kDa amyl ...[more]

PMID: 25023329

Similar Datasets

Project description:BackgroundHereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework.ResultsThe updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70-74 years, for which it was 0.96.ConclusionsAGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.

Dataset Information

Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model.

Publications

Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets