In case of prion infection in humans or animals, the point of entry is outside the nervous system. TTtic march of prions into the CNS (“neuroinvasion”) may involve the lymphoreticular or autonomic nervous system.40 Together, prion diseases are caused by aggregation of prion proteins, most likely initiated by conversion of a physiological

conformation (PrPC) into an infectious form (PrPSc), which serves as a seed that induces polymerization,45 formation Inhibitors,research,lifescience,medical of fibrils, and deposition. Neurotoxicity of protein aggregates AD, FTD, DLB, and prion diseases share the deposition of abnormally folded proteins as a common denominator. All of these diseases occur predominantly sporadically with a minor portion caused by mutations associated with familial forms Inhibitors,research,lifescience,medical of the disease. The formation of aggregates may be a desperate attempt to eliminate the

toxicity of misfolded proteins and their oligomeric or fibrillar states. The pathogenetic mechanisms entail abnormal proteolytic cleavage, posttranslational processing, misfolding, and reduced clearance of protein aggregates. The dissection of the kinetics of folding and deposition, the folding intermediates, Inhibitors,research,lifescience,medical and promoting Inhibitors,research,lifescience,medical factors will be crucial for the discovery of new therapeutic targets. The variety of protein species that are capable of forming β-pleated sheets, deposit into amyloid, and induce neurodegeneration suggests an inherent neurotoxicity of protein aggregates. Interestingly, a range of proteins not associated with amyloid diseases are also able to aggregate in vitro into fibrils barely distinguishable from those found in pathological conditions.46-48 Thus, aggregation may be viewed as a general property of polypeptide chains Inhibitors,research,lifescience,medical that occurs in a specific environment. Whether this process ends up in neurodegeneration may depend on

the selective Terminal deoxynucleotidyl transferase vulnerability determined by age-related cellular alterations, genetic background, and capacity of removal and repair mechanisms. The neuronal cell possesses a defense machinery, eg, chaperones, which protects against protein misfolding, a process that occurs, like DNA replication errors, permanently during protein synthesis and transport.49 Imperfectly produced proteins are degraded by a sort of clearance AG-14361 clinical trial pathway, such as the ubiquitin-proteasome system.50 Dysfunction of both the protein folding defense system and the degrading system of defective proteins may also contribute to the development of neurodegenerative diseases.