‘Neurodegenerative’ refers to the pathological changes in the brain, resulting from loss of neurons, ultimately leading to deterioration of brain function. At a cellular level, neurodegeneration is seen as a gradual loss of structure or function of neurons leading to neuronal death. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, multiple sclerosis, Als lateral sclerosis and Huntington’s disease occur as a result of neurodegenerative disorders (Minagar, Shapshak et al. 2002, Pryce, Ahmed et al. 2003, Romero and Rodríguez Luque 2011). The hallmark of many neurodegenerative diseases is the accumulation of intracellular or extracellular protein. Some studies in vitro and in vivo have provided new visions into neurodegeneration disorders, furthering understanding of the mechanisms regulating
protein processing, specifically neurodegenerative disease proteins. The
understanding of such disorders facilitates the development of therapies, that may prevent occurrence of severe memory loss, communication problems or the aforementioned diseases (Zecca, Youdim et al. 2004). These types of diseases belong to the category of dementias which result in cognitive deficits (loss of cognitive ability as a result of a brain injury (Dementia and MCI , Robinson 1998, Schneider, Wilson et al. 2003).
6.3.1 Anti-Inflammatory role of PPARs in neurodegenerative disorders
Recent studies point towards the role of peroxisome proliferator activated receptors in protecting against inflammation, particularly in the central nervous system. New evidence has shown a beneficial effect of targeting peroxisome proliferators activated receptor gamma PPAR- , to improve the outcomes of neurodegenerative disease. Several recent studies have shown that PPAR- agonists inhibit neuronal degeneration. For example; oral treatment with potent PPAR- agonists such as telmisartan, provides neuro-protection against cell death and neuro-inflammation (Shoelson, Lee et al. 2006, Akaike, Takada-Takatori et al. 2010).
Chapter 6 Introduction
6.3.2 Neuro-inflammation in parkinsons’ disease (PD), Alzheimer (AD) and Sclerosis
Most of the studies performed on the PPAR- receptor have been in relation to the microglia, to understand its role during inflammation. Studies on astrocytes are less abundant (Carta and Pisanu 2012). The present study focuses on the role of astrocytes, and understanding how they are activated to proliferate, ultimately resulting in neurodegenerative disorders.
6.3.2.1 Alzheimer disease and microglial phagocytic role
Studies suggest that Alzheimer's disease (AD) is associated with age, gender and varies between brain regions. The cause and progression of Alzheimer's disease is not well understood. Alzheimer’s disease involves glial inflammation associated with amyloid plaques in the grey matter of the brain. This would lead to abundance of microglia, and astrocytes, leading to progressive neuronal degeneration and ultimately death (Lipton 2005). The role of the microglial cells in the AD brain is controversial, as it remains unclear whether the microglia form the amyloid plaques or react to them in a macrophage-phagocytic role. Some evidence has shown the role of phagocytosis by microglia in the brain, although there is also evidence that microglia show differential selection to specific types of amyloid plaque in the AD brain. This may explain why microglia are sensitive to the presence of foreign bodies (McGeer, Itagaki et al. 1988, Wyss-Coray and Mucke 2002).
6.3.2.2 Parkinson's disease
Parkinson's disease is a degenerative disorder in the central nervous system characterised by loss of dopaminergic neurons in the extrapyramydal motor system. The pathology of the disease is characterized by the gathering of a protein called - synuclein into Lewy bodies in neurons. The -synuclein gene was identified as the main element of Lewy bodies. Lewy bodies (LBs) cause gradual degeneration of
Chapter 6 Introduction
neurons progressing to full Parkinson’s disease. The ubiquitin proteasome system (UPS) became the most important way to verify the mechanism of PD. The UPS is a highly regulated and controlled system, thereby avoiding protein degradation in the brain (Olanow, Kieburtz et al. 2008).
6.3.2.3 Ubiquitin Proteasome System
Proteasomes are very large protein complexes, found inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The cells of organisms work hard to maintain the healthy balance of proteins. The main function of the proteasome is to degrade unwanted or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Their important regulatory role is carried out by the ubiquitin proteasome system (UPS). Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids, to be used in synthesizing new proteins. In a sense, the UPS is responsible for detecting destroyed or faulty proteins. Proteins are tagged for degradation with a small protein called ubiquitin, (Figure 6-8). The tagging reaction is catalyzed by enzymes called ubiquitin ligases.
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling. Ubiquitin binds to proteins and labels them for destruction. The ubiquitin tag directs proteins to the proteasome, which is a large protein complex in the cell that degrades and recycles unwanted proteins. Once a protein is tagged with a single ubiquitin molecule (monoubiquitination) or many (polyubiquitination), this is a signal to other ligases to attach additional ubiquitin molecules. The result is a poly-ubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein (Rogers, Paine et
Chapter 6 Introduction
Therefore, the UPS can be over-active, whereby useful proteins are destroyed, or underactive, causing harmful proteins to build up to toxic levels. Homeostasis requires the right amount a specific protein at the right time (Kimura and Tanaka 2010). Failure of the ubiquitin proteasome system can result in diseases such as; Alzheimer’s disease, infectious diseases, some cancers and inflammatory diseases such as Rheumatoid (Oddo 2008, Moreau, Luo et al. 2010).
Figure 6-8 Diagram of the 26S proteasome structure.
The 26S proteasome system composes of two sub-complexes: a 20S core particle that carries the catalytic activity, and a regulatory 19S regulatory particle. Ubiquitination and degradation processes undergoing three steps to degrade misfolded proteins. (E1) activates and binds to ubiquitin. The activated ubiquitin is transferred to a cysteine group, an ubiquitin-conjugating enzyme (E2). Then, the ubiquitin is transferred to the substrate by the action of an ubiquitin ligase enzyme (E3). Depletion of 26S proteasomes in mouse brain neurons showes 26S proteasomal dysfunction caused neurodegeneration (Ciechanover 2005).
Chapter 6 Introduction