Pituicytoma with Gelsolin Amyloid Deposition

Ida, Cristiane M.; Yan, Xiaoqian; Jentoft, Mark E.; Kip, N. Sertac; Scheithauer, Bernd W.; Morris, Jonathan M.; Doğan, Ahmet; Parisi, Joseph E.; Kovács, K.

doi:10.1007/s12022-013-9254-y

Cited by 15 publications

(13 citation statements)

References 45 publications

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“…In the last five years, the broader clinical use of genetic tests and the raised awareness of this class of diseases led to the identification of three new AGel forms. A new classification of the disease into three different types, according to the GSN sequence and the organ(s) involved in amyloid deposition, has been therefore proposed and includes: i) a systemic form, caused by D187N and D187Y mutations, respectively known as the Finnish-and Danish-variant; ii) a kidney localized form, associated with the deposition of GSN, either full-length or as fragments, carrying N184K or G167R mutation [5][6][7]; and iii) a sporadic form, caused by wild-type (WT) GSN deposits surrounding a sellar glioma of the hypophysis [8]. All AGel types share the lack of effective pharmacological therapies that cure the disease targeting the source of toxicity, rather than acting only as palliative, symptomatic treatments.…”

Section: Introductionmentioning

confidence: 99%

Nanobody interaction unveils structure, dynamics and proteotoxicity of the Finnish-type amyloidogenic gelsolin variant

Giorgino

Mattioni

Hassan

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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§ These authors contributed equally to this work. Highlights• D187N gelsolin variant is responsible for the most common form of AGel amyloidosis • We obtained the crystal structure of the second domain of D187N in complex with a nanobody• D187N substitution increases the conformational flexibility of the protein • Nanobody binding shifts D187N towards a native-like conformation• The same nanobody binds to and protects other gelsolin pathological variants (N184K and G167R)• The nanobody protects from the toxicity induced by gelsolin mutants in C. elegans AbstractAGel amyloidosis, formerly known as familial amyloidosis of the Finnish-type, is caused by pathological aggregation of proteolytic fragments of plasma gelsolin. So far, four mutations in the gelsolin gene have been reported as responsible for the disease. Although D187N is the first identified variant and the best characterized, its structure has been hitherto elusive. Exploiting a recently-developed nanobody targeting gelsolin, we were able to stabilize the G2 domain of the D187N protein and obtained, for the first time, its high-resolution crystal structure. In the nanobody-stabilized conformation, the main effect of the D187N substitution is the impairment of the calcium binding capability, leading to a destabilization of the C-terminal tail of G2. However, molecular dynamics simulations show that in the absence of the nanobody, D187N-mutated G2 further misfolds, ultimately exposing its hydrophobic core and the furin cleavage site. The nanobody's protective effect is based on the enhancement of the thermodynamic stability of different G2 mutants (D187N, G167R and N184K). In particular, the nanobody reduces the flexibility of dynamic stretches, and most notably decreases the conformational entropy of the Cterminal tail, otherwise stabilized by the presence of the Ca 2+ ion. A Caenorhabditis elegans-based assay was also applied to quantify the proteotoxic potential of the mutants and determine whether nanobody stabilization translates into a biologically relevant effect. Successful protection from G2 toxicity in vivo points to the use of C. elegans as a tool for investigating the mechanisms underlying AGel amyloidosis and rapidly screen new therapeutics.

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Section: Introductionmentioning

confidence: 99%

Nanobody interaction unveils structure, dynamics and proteotoxicity of the Finnish-type amyloidogenic gelsolin variant

Giorgino

Mattioni

Hassan

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In this regard, actin binding proteins such as gelsolin and vimentin have been shown to participate in actin remodeling, a process known to enhance the formation of cell protrusive structures and thus metastatic phenotypes [52-56]. Therefore, in the current study, we tested the hypothesis that DHA treatment would alter the expression of the actin binding proteins gelsolin and vimentin and thus suppress the metastatic phenotype.…”

Section: Discussionmentioning

confidence: 99%

DHA-mediated regulation of lung cancer cell migration is not directly associated with Gelsolin or Vimentin expression

2016

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AIMS Deaths associated with cancer metastasis have steadily increased making the need for newer, anti-metastatic therapeutics imparative. Gelsolin and vimentin, actin binding proteins expressed in metastatic tumors, participate in actin remodelling and regulate cell migration. Docosahexaenoic acid (DHA) limits cancer cell proliferation and adhesion but the mechanisms involved in reducing metastatic phenotypes are unknown. We aimed to investigate the effects of DHA on gelsolin and vimentin expression, and ultimately cell migration and proliferation, in this context. MAIN METHODS Non-invasive lung epithelial cells (MLE12) and invasive lung cancer cells (A549) were treated with DHA (30 μmol/ml) or/and 8 bromo-cyclic adenosine monophosphate (8 Br-cAMP) (300 μmol/ml) for 6 or 24 h either before (pre-treatment) or after (post-treatment) plating in transwells. Migration was assessed by the number of cells that progressed through the transwell. Gelsolin and vimentin expression were measured by western blot and confocal microscopy in cells, and by immunohistochemistry in human lung cancer biospy samples. KEY FINDINGS A significant decrease in cell migration was detected for A549 cells treated with DHA verses control but this same decrease was not seen in MLE12 cells. DHA and 8 Br-cAMP altered gelsolin and vimentin expression but no clear pattern of change was observed. Immunoflorescence staining indicated slightly higher vimentin expression in human lung tissue that was malignant compared to control. SIGNIFICANCE Collectively, our data indicate that DHA inhibits cancer cell migration and further suggests that vimentin and gelsolin may play secondary roles in cancer cell migration and proliferation, but are not the primary regulators.

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“…Pituicytomas generally consist of bipolar spindle cells with occasional intermediate filaments and rare mitotic figures . Immunohistochemical analysis shows a general positivity for glial fibrillary acidic protein (GFAP), thyroid transcription factor 1 (TTF1), and S100, as well as an occasional positivity for vimentin . Recently positivity for vascular endothelial growth factor (VEGF) has been described .…”

Section: Introductionmentioning

confidence: 99%

“…The term pituicytoma was first introduced by Liss in 1958 1 describing a tumor of the posterior pituitary gland. It is generally thought to be a rare neoplasm of the sellar region (MRI sequence, Figure 1 3 Immunohistochemical analysis shows a general positivity for glial fibrillary acidic protein (GFAP), thyroid transcription factor 1 (TTF1), 5,6 and S100, 3 as well as an occasional positivity for vimentin. 7 Recently positivity for vascular endothelial growth factor (VEGF) has been described.…”

Section: Introductionmentioning

confidence: 99%