Abstract
Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses. These include both localized (e.g. Alzheimer’s disease, prion diseases, type 2 diabetes mellitus) and systemic amyloidoses. Historically regarded as a group of maladies with limited, even inexistent, therapeutic options, some forms of systemic amyloidoses have recently witnessed a series of unparalleled therapeutic successes, positively impacting on their natural history and sometimes even on their incidence. In this review article we will revisit the most relevant of these accomplishments. Collectively, current evidence converges towards a crucial role of an early and conspicuous reduction or stabilization of the amyloid-forming protein in its native conformation. Such an approach can reduce disease incidence in at risk individuals, limit organ function deterioration, promote organ function recovery, improve quality of life and extend survival in diseased subjects. Therapeutic success achieved in these forms of systemic amyloidoses may guide the research on other protein misfolding and deposition diseases for which effective etiologic therapeutic options are still absent.
Highlights
Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses
#Systemic amyloid deposits can be observed in some forms of prion diseases, including variant Creutzfeldt-Jacob disease and in PrP systemic amyloidosis
Amyloidosis can be caused by genetic mutations which destabilize an otherwise non-amyloidogenic or only mildly amyloidogenic protein, as in familial prion diseases and hereditary systemic amyloidoses (Connors et al, 2003; Rowczenio et al, 2019), or by mutations which increase the synthesis or the proteolytic release of the amyloid-forming protein, as in the case of AA amyloidosis associated to hereditary autoinflammatory syndromes or familial Alzheimer’s disease, respectively (De Strooper et al, 2012; Obici and Merlini, 2012)
Summary
Protein misfolding and deposition diseases arise when one of an ever growing list of proteins (the amyloid-forming protein in its native conformation, referred to as the amyloidogenic precursor) acquires an alternative folding state (the misfolded state), starts to aggregate and to form oligomers, protofibrils and fibrillar structures (termed amyloid fibrils) which eventually deposit within tissues (forming the amyloid deposits) (Benson et al, 2018a). Amyloid deposition can affect multiple body sites (typically sparing the central nervous system parenchyma) when the amyloid-forming protein is a circulating protein, as in the case of systemic amyloidoses (Nuvolone and Merlini, 2017b) (Table 1). The prion protein can form amyloid deposits outside of the CNS in the presence of selected mutations of the PRNP gene, leading to PrP
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