Protein Folding in Neurodegenerative Diseases

        Protein folding is a key biological process which is crucial for cellular viability that ensures the presence of constant levels of proteins within the cell (). Proteins need to be folded correctly into three dimensional conformations in order to be specified to carry out certain biological processes (Dobson, 2003; ). However, proteins tend to misfold into abnormal structures in response to particular circumstances, whereby environmental factors or mutations may augment protein misfolding (). Newly synthesized proteins are constantly monitored by cellular systems, called protein quality control (PQC), in order to ensure that the proteins are being folded into proper conformations ().        

        Chaperones are a group of proteins that involve in PCQ to inhibit the misfolding of proteins. There are two types of molecular chaperones involved in blocking the aggregation of misfolded proteins, namely heat shock proteins (Hsps) which are found in cytosol and protein disulphide isomerase (PDI) family of proteins which are found in the endoplasmic reticulum (Barral, 2004). Protein misfolding is a crucial pathological hallmark of neurodegenerative diseases, whereby the abnormal proteins aggregate in targeted regions of the nervous system and inhibit essential cellular activities. In this write up, different types of misfolded proteins and the mechanisms involved in the pathogenesis of two neurodegenerative diseases, namely amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), will be discussed.    

        First and foremost, the pathogenesis of amyotrophic lateral sclerosis (ALS) will be scrutinized. ALS targets both lower and upper motor neurons of the brainstem, cortex, and spinal cord (Paez-Colasante, 2015). The hallmarks of this disease are muscle weakness, muscle atrophy, paralysis, and eventually fatality due to failure in respiratory system (), generally within 3-5 years post diagnosis. ALS is known as protein misfolding disorder because researchers have identified the presence of insoluble inclusions of misfolded proteins in the brain stem and spinal cord, as well as in the frontal and temporal cortices, hippocampus, thalamus, and cerebellum (Al-Chalabi, 2012; Watanabe et al., 2001; Zhang, 2014c). Some researchers have claimed that the large inclusions are somewhat harmless because they may not be toxic to the neurons and may be responsible in neuroprotective phenomenon (Guo et al., 2010; ). In contrary, the small, oligomeric forms of misfolded proteins were said to be toxic to the cells (; Guo et al., 2010).

        There are several major misfolded proteins that are involved in the pathogenesis of ALS, including Superoxide dismutase 1 (SOD 1), TAR-DNA binding protein-43 (TDP-43), and Fused in Sarcoma (FUS) protein. SOD 1 is primarily found in cytoplasm and nucleus (), whereby it catalyzes the reduction of harmful, free superoxide radicals into molecular oxygen and hydrogen peroxide (). Over 160 different ALS-linked SOD1 mutations have been examined by the researchers (Saccon, 2013). Mutant SOD1 proteins have a highly destabilized structure and can be reduced into monomers (Saccon, 2013). They have also been hypothesized to be involved in the impairment of axonal and cellular transport, disruption of calcium homeostasis, RNA dysfunction, mitochondrial damage and dysregulation to autophagy (Bunton-Stasyshyn, 2014).      

        On the other hand, TDP-43 is a multifunctional RNA- and DNA-binding protein which has a glycine-rich C-terminus comprised of prion-like domain (Kato et al., 2012). This C-terminal is prone to aggregation and was found to induce cellular toxicity when the researcher studied yeast models (Johnson, 2008). In addition, ALS mutations have also been indicated to cluster around the C-terminus of TDP-43 (Rutherford, 2008; Sreedharan, 2008). FUS has structural and functional similarities to TDP-43, and over 46 ALS-linked FUS mutation have been indicated. In contrast to FDP-43, FUS comprised of a glycine rich region at its N-terminal and has prion-like domain that determines the aggregation of FUS (Sun, 2011). Post mortem analysis of brain and spinal cord tissues of ALS patients with FUS mutations signified that there are abnormal cytoplasmic inclusions containing FUS were present in neurons and glial cells. This was thought to be due to absence of post-translational modifications such as hyperphosphorylation and ubiquitination (Kwiatkowski, 2009; Vance, 2009 ).

        These misfolded proteins lead to pathogenic mechanisms in ALS through ‘prion-like’ propagation of toxicity. Recent findings through in vitro models indicate that mutant SOD1 displays prion-like properties, despite not containing a specific prion-like domain (; L. I. Grad, et al., 2011, 2014). Prion proteins have similar composition of amino acid to yeast prion proteins, thus, they have high propensity to aggregate. In addition, aggregated TDP-43 that has been isolated from the brains of ALS patients and then applied to human neuroblastoma cells in culture, serves as a seed for propagation for further aggregation (Nonaka et al., 2013). The induced intracellular aggregated TDP-43 was shown to be toxic to the neuronal cell cultures (Pokrishevsky, 2012). The types of protein misfolds and the pathogenic mechanisms involved in ALS have been discussed. Next, protein misfolding in Huntington’s disease will be deliberated.

        Huntington’s disease (HD) is a rare, autosomal dominant and progressive neurodegenerative disease (Bates, 2003; Menzies et al., 2009; Thomson et al., 1998). The diagnosis is made based on the clinical presentation of behavioral and psychiatric features, cognitive, and motor manifestations of the disease, as well as the presence of a positive family history (J.-P. Vonsattel et al., 1985). HD can be identified using genetic testing because it has been found that an abnormal increase in CAG repeats in the first exon of huntingtin (htt) gene, which encodes for polyQ stretch in the HTT protein. Long polyQ tracts may possibly disrupt the normal function of cellular proteins, and this mechanism underpins the pathogenesis of HD (McNeil et al., 1997). Several studies have shown that the mutant HTT protein with expanded CAG repeats implicated in a number of cellular processes, such as transcriptional deregulation mitochondrial dysfunction, and impaired vesicle transport (; ; ).