Gelsolin Amyloidosis as a Cause of Early Aging and Progressive Bilateral Facial Paralysis

Pihlamaa, Tiia; Rautio, Jorma; Kiuru-Enari, Sari; Suominen, Sinikka

doi:10.1097/prs.0b013e318213a0a2

Cited by 31 publications

(36 citation statements)

References 34 publications

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“…Since the first report of the disease, patients have been found in many countries, including the United States, Japan, Portugal, England, Germany, Spain, France, Brazil, Sweden, Denmark, the Czech Republic, and Iran. (Conceicao et al, 2003, Pihlamaa et al, 2011, Huerva et al, 2007, Stewart et al, 2000, Ikeda et al, 2007, Tanskanen et al, 2007, Chastan et al, 2006, Contegal et al, 2006, Luettmann et al, 2010, Ardalan et al, 2007, Makioka et al, 2010, Kiuru, 1998, Carrwik and Stenevi, 2009, Felix et al, 2008, Plante-Bordeneuve and Said, 2011). Many of the patients studied had no Finnish ancestors, suggesting multiple founders of the disease.…”

Section: History and Epidemiology Of Gelsolin Amyloidosismentioning

confidence: 99%

“…In addition, the natural history of the disease, including the frequency with which each of the described symptoms present is unknown because of the rarity of the disease. However, there is clearly a severe morbidity associated with FAF (Carrwik and Stenevi, 2009, Pihlamaa et al, 2011). …”

Section: Clinical Presentations Of Familial Amyloidosis Of Finnish Typementioning

confidence: 99%

“…As the disease progresses, many patients opt to undergo plastic and reconstructive surgery to improve the facial appearance caused by amyloid deposition in the basement membrane of the skin. Brow lifts to alleviate brow ptosis and blepharoplasties to remove thickened skin in the eyelids are often performed, along with forehead lifts and face lifts (Pihlamaa et al, 2011). Multiple surgeries are often required as FAF progresses.…”

Section: Clinical Presentations Of Familial Amyloidosis Of Finnish Typementioning

confidence: 99%

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Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Solomon

Page

Balch

et al. 2012

Critical Reviews in Biochemistry and Molecular Biology

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Protein misassembly into aggregate structures, including cross-β-sheet amyloid fibrils, is linked to diseases characterized by the degeneration of post-mitotic tissue. While amyloid fibril deposition in the extracellular space certainly disrupts cellular and tissue architecture late in the course of amyloid diseases, strong genetic, pathological and pharmacologic evidence suggests that the process of amyloid fibril formation itself, known as amyloidogenesis, likely causes these maladies. It seems that the formation of oligomeric aggregates during the amyloidogenesis process causes the proteotoxicity and cytotoxicity characteristic of these disorders. Herein, we review what is known about the genetics, biochemistry and pathology of familial amyloidosis of Finnish Type (FAF) or gelsolin amyloidosis. Briefly, autosomal dominant D187N or D187Y mutations compromise Ca2+ binding in domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations. When domain 2 is unfolded, gelsolin is subject to aberrant furin endoproteolysis as it passes through the Golgi on its way to the extracellular space. The resulting C-terminal 68kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin. These amyloidogenic fragments deposit systemically, causing a variety of symptoms, including corneal lattice dystrophy and neurodegeneration. The first murine model of the disease recapitulates the aberrant processing of mutant plasma gelsolin, amyloid deposition, and the degenerative phenotype. We use what we have learned from our biochemical studies, as well as insight from mouse and human pathology to propose therapeutic strategies that may halt the progression of FAF.

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Section: History and Epidemiology Of Gelsolin Amyloidosismentioning

confidence: 99%

Section: Clinical Presentations Of Familial Amyloidosis Of Finnish Typementioning

confidence: 99%

Section: Clinical Presentations Of Familial Amyloidosis Of Finnish Typementioning

confidence: 99%

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Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Solomon

Page

Balch

et al. 2012

Critical Reviews in Biochemistry and Molecular Biology

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“…14 Therapy is currently restricted to symptomatic treatment such as eyedrops, management of intraocular pressure and plastic surgery. 15,16 A mouse model of gelsolin amyloidosis recapitulates the endoproteolytic cascade and associated amyloid deposition. 17 Llama VHH antibodies or nanobodies correspond to the variable part of heavy chain antibodies.…”

Section: Introductionmentioning

confidence: 99%

Chaperone Nanobodies Protect Gelsolin Against MT1-MMP Degradation and Alleviate Amyloid Burden in the Gelsolin Amyloidosis Mouse Model

et al. 2014

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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.

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“…Most important is good ophthalmological care ranging from eye drops to corneal transplantation. Next to that, aesthetic surgery is often needed to ameliorate the patients' overall confidence as the facial pareses and cutis laxis burden the patients with a constant droopy facial expression [31].…”

Section: Diagnosis and Treatmentmentioning

confidence: 99%

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

Verhelle¹,

Gettemans²

2016

Exploring New Findings on Amyloidosis

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Gelsolin amyloidosis (AGel) is an autosomal-dominant inherited disease caused by point mutations in the gelsolin gene. At the protein level, these mutations result in the loss of a Ca 2+ -binding site, crucial for the correct folding and function. In the trans-Golgi network, this mutant plasma gelsolin is cleaved by furin, giving rise to a 68 kDa Cterminal fragment. When secreted in the extracellular matrix, this fragment undergoes proteolysis by MT1-MMP-like proteases, resulting in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies, the variable part of the heavy chain of heavychain antibodies, have been used as molecular chaperones for mutant plasma gelsolin and the 68 kDa C-terminal fragment in an attempt to inhibit their pathogenic proteolysis. Furthermore, these nanobodies have also been tested and applied as a 99m Tc-based imaging agent in the gelsolin amyloidosis mouse model.

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Gelsolin Amyloidosis as a Cause of Early Aging and Progressive Bilateral Facial Paralysis

Abstract: Operative treatment of gelsolin amyloidosis is symptomatic. Due to relentless disease progression, a good functional and aesthetic result seems to require selected techniques and repeated surgery. Recognizing this underdiagnosed syndrome is essential.

Cited by 31 publications

References 34 publications

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Chaperone Nanobodies Protect Gelsolin Against MT1-MMP Degradation and Alleviate Amyloid Burden in the Gelsolin Amyloidosis Mouse Model

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

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