Molecular Research in Endoplasmic Reticulum Storage Diseases and Related Disease

Dear Colleague,

This issue of IJMS is dealing with the main endoplasmic reticulum storage diseases (ERSD), Alpa-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS).

Molecular and genetic studies have unraveled the pathomorphogenesis of the basic disease process, i.e., plasma deficiency and accumulation in the hepatocyte ER of mutant proteins causing liver cell injury and progressive liver disease.

Mutations in AAT and Fibrinogen genes provoke conformational abnormalities and polymerization in the form of grotesque polypeptide arrays which result in fantastic molecular images of the 3D structure.

In addition, the discovery of AATD has disclosed the basic mechanism of pulmonary emphysema.

A few topics are devoted to therapeutic perspectives whose rationale is suggested by the detection of mutant ZAAT by serum IF as proof that ZAAT polymers can be exported to some extent, and by the demonstration of polymerized mutant proteins (either homo- or hetero-polymers) within the RER as an indication that the storage process is a very early event in protein synthesis.

Thus, small molecules are being selected and tested in vitro, in animal models, and in vivo for their capability of reducing the amount of storage, either by binding the cleaved ZAAT at the polymerization interphase to inhibit aggregation, or by enhancing its degradation.

Molecular research is expected to clarify a few features of HHHS: (a) only mutations in the gamma chain predispose to storage; (b) mutant gamma chains are not found in circulation; (c) hypo-fibrinogenemia does not result in overt extrahepatic clinical manifestations; (d) intrahepatic fibrinogen polymers can bind other molecules to form allopolymers.   

Prof. Dr. Francesco Callea
Guest Editor

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