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Abnormal TTR levels are found in neuropathologies such as Guillain-Barré syndrome (GBS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), amd Parkinson’s disease (PD)<ref name= "Vieira" />. | Abnormal TTR levels are found in neuropathologies such as Guillain-Barré syndrome (GBS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), amd Parkinson’s disease (PD)<ref name= "Vieira" />. | ||
Additionally, there is another defect related to TTR, which is more probable and known: the formation of amyloid fibrils. It can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID | Additionally, there is another defect related to TTR, which is more probable and known: the formation of amyloid fibrils. It can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID 25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> P.Gambetti, C. Russo. Human brain amyloidoses. Neuphrol Dial Transplant. 1998; 13 [Suppl 7] : 33-40</ref> | ||
Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" /> | Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" /> | ||
TTR aggregation into amyloid fibrils leads to insolubility. Consequently, it creates abnormal deposits in the peripheral nerves in the case of FAP, in the central nerves for CNSA, and in heart tissues for FAC and SSA. Therefore, the insoluble proteins alter the corresponding organ and tissue functions, and are unable to be subjected to a proper degradation by cell metabolism. | TTR aggregation into amyloid fibrils leads to insolubility. Consequently, it creates abnormal deposits in the peripheral nerves in the case of FAP, in the central nerves for CNSA, and in heart tissues for FAC and SSA. Therefore, the insoluble proteins alter the corresponding organ and tissue functions, and are unable to be subjected to a proper degradation by cell metabolism. | ||
In most of the cases, autosomal dominant mutations of the TTR gene are at the origin of the Human familial amyloidosis (FAP, FAC, CNSA) through TTR conformational disorder. Val30Met is the most recensed amyloidogenic point mutation observed ([[4tl4]]). However, SSA differentiates from these TTR-related hereditary amyloidosis by usually affecting patients in advanced age, as it involves an aggregate formation due to a progressive accumulation of wild-type TTR proteins mainly associated to misshaping and beta-strand lacking <ref> Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ (April 2013). "Senile systemic amyloidosis: clinical features at presentation and outcome". Journal of the American Heart Association. 2 (2): e000098. PMC 3647259. PMID 23608605 doi: http://dx.doi.org/10.1161/JAHA.113.000098 </ref><ref> Gustavsson A. Jahr H, Tobiassen R, Jacobson DR, Sletten K, Westermark P. Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis. 1995 Nov; 73(5):703-8 </ref> | In most of the cases, autosomal dominant mutations of the TTR gene are at the origin of the Human familial amyloidosis (FAP, FAC, CNSA) through TTR conformational disorder. Val30Met is the most recensed amyloidogenic point mutation observed ([[4tl4]]). However, SSA differentiates from these TTR-related hereditary amyloidosis by usually affecting patients in advanced age, as it involves an aggregate formation due to a progressive accumulation of wild-type TTR proteins mainly associated to misshaping and beta-strand lacking <ref> Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ (April 2013). "Senile systemic amyloidosis: clinical features at presentation and outcome". Journal of the American Heart Association. 2 (2): e000098. PMC 3647259. PMID 23608605 doi:http://dx.doi.org/10.1161/JAHA.113.000098 </ref><ref> Gustavsson A. Jahr H, Tobiassen R, Jacobson DR, Sletten K, Westermark P. Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis. 1995 Nov; 73(5):703-8 </ref> | ||