Protein misfolding and neurodegeneration ; new approaches to combat toxic misfolded proteins

Introduction The proteins are manifestation of the genetic functions and are central to various biological processes. Misfolded proteins may lead to pre-fibrillar assemblies and and can cause destabilizing mutations on disease proteins. Protein folding has been studied in detail by both experimental and theoretical methods (Soto & Estrada, 2008). Human diseases characterized by insoluble deposits of proteins have been recognized for more than 180 years. The misfolding and aggregation of proteins implicated in neurodegenerative diseases has been modeled in vitro. There is no evident sequence or structural homology among the proteins involved in diverse neurodegenerative diseases. This diverse group of diseases includes common disorders such as Alzheimer’s disease (AD) and Parkinson disease (PD) and rarer disorders such as Huntington’s disease, spinocerebellar ataxia, transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis. The toxic proteins responsible for the various neurodegenerative disorders have been nicely depicted in Table 1 (Bertolotti, 2007). Despite the significant differences in clinical manifestation, neurodegenerative disorders share some common features such as their appearance late in life, the extensive neuronal loss and synaptic abnormalities, and the presence of cerebral deposits of misfolded protein aggregates. Misfolded toxic proteins cause irreversible damage by prolonged ER stress triggers an apoptotic program that includes the induced C/EBP-homologous transcription factor (CHOP) (Kaufman, 1999), activation of cJun N-terminal kinases (JNK) (Urano et al., 2000), and cleavage of the UPR specific cysteine protease, caspase-12 (Nakagawa and Yuan, 2000). Recent findings suggest that the intrinsically lower ubiquitin-proteasome system (UPS) activity in neurons is a major contributor to the preferential accumulation of misfolded proteins in neurons seen in various neurodegenerative diseases. Addressing this enigma could help explain the mechanisms behind the selective neuropathology in a variety of neurodegenerative disorders that are caused by misfolded proteins. This review covers these aspects of protein misfolding and neurodegeneration along with strategies to combat these issues for curative purpose. Protein misfolding and chemical chaperones There are some important examples of chemical chaperones for preventing damage by misfolded toxic proteins. Probably the best known example of protein misfolding that is responsible for a disease is the ∆F508 mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which causes cystic fibrosis. The ∆F508 allele of CFTR has been confirmed as a trafficking mutation that blocks the maturation of the protein in the ER and targets it for premature proteolysis (Dalemans et al 1991). However, if the ∆F508 protein is redirected to the cell surface, cAMP-mediated transport can be restored. The clinical importance of this mutation becomes evident when considering that the ∆F508 mutation accounts for nearly 70% of patients diagnosed with cystic fibrosis (Brown et al 1996). When overexpressed in heterologous systems, the ∆F508 mutation leads to the appearance of a small number of functional CFTR Cl2 channels in the plasma membrane. As a result of this observation, it has been proposed that some nascent ∆F508 molecules can fold correctly, thereby escaping degradation. Interestingly, Xenopus oocytes and mammalian cells incubated at reduced (20–30°C) temperatures, express more ∆F508 molecules at the cell surface than those incubated at standard temperatures. At these lower temperatures, a fivefold increase in cAMP-stimulated whole-cell currents was detected. As relating to the Alzheimer’s disease Aβ has emerged as the most promising target in the treatment or prevention of AD. Inhibition of fibril formation might be a reasonable therapeutic strategy because familial mutations that lead to an increase in Aβconcentration or to its aggregation increase neuropathology (Makin and Serpil, 2002). Unfortunately, no effective therapy