Dept. of Biomedical Sciences and Technologies, University of Cagliari, Italy
Director: Prof. Paolo La Colla

Neurodegenerative diseases and protein misfolding:

new inhibitors and novel targets

*Christina D. Orrù., *M. Dolores Cannas, *Marco Basciu, *Francesca Manconi,

*Sarah Vascellari.
°Claudia Abete, °Claudia Mulas, °Claudia Norfo, °Marirosa Putzolu, °Anna Saba.

*Section of General Microbiology and Virology and Microbial Biotechnologies

°Section of Experimental Pathology

Background & Objectives. Prion disorders (or Transmissible Spongiform Encephalopathies, TSE), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD), are the most well known neurodegenerative diseases characterized by cellular protein’s conformational transition from an -helix structure to a -sheet structure that preludes to aggregation and fibril formation. Although they may have different origins (sporadic, familiar or transmissible), these pathologies are also known as conformational diseases or protein misfolding diseases, in order to emphasize misfolded proteins as a possible cause of their clinical symptoms. Proteins that distinguish TSE, AD, PD and HD, although not having amino acid sequence homology, show the same susceptibility to conformational conversion, fibrilar structure formation, and proteolysis resistance in vitro and in vivo. Consequently, the development of drugs able to over stabilize the secondary -helix structure and/or inhibit protein’s -sheet conversion represent a therapeutic approach of increasing scientific attention. There is now increasing evidence that modifications in cholesterol homeostasis may be involved in the conformational changes underlying the formation of amyloid plaques in AD and TSE. It is our opinion that biochemical and molecular investigations aimed at elucidating the role of cholesterol homeostasis in the pathogenesis of these pathologies, may lead to the description of a cell phenotype possibly predisposing to misfolding protein formation/deposition, together with the identification of novel targets for anti-amyloid therapies. Methods.Studies are performed in ”in vitro” models of AD and TSE; i.e. fibroblasts and PBMC of AD patients, their relatives and healthy donors, for AD, and mouse neuroblastoma (MNB) cells persistently infected mouse-adapted scrapie as well as fibroblasts and PBMC from uninfected and scrapie-infected sheep, for TSE. The same models are used for the evaluation of: i) the molecular biology of mRNAs and proteins involved in cholesterol transport and/or trafficking; ii) the inhibitory effect of modulators of cholesterol esterification, either alone or in combination with both known and novel anti-protein misfolding compounds, on the amyloid deposition and prion (PrPSc) accumulation. Results. Results obtained so far cannot be yet reported, since they are presently under intellectual protection in the following international patent application: Anchisi C, Dessì S, La Colla P, Pani A. “Methods for diagnosis and treatment of proliferative or conformational diseases.” Patent Application (provisional) USA, 2/17/06