Recent Advances in the Study of Protein Misfolding Diseases

Alzheimer 's disease (AD) was discovered by a German doctor Alois Alzheimer in 1906 when he found amyloid plaques and neurofibrillary tangles in the autopsy of a woman who died of an unknown mental disease. The extracellular amyloid plaque deposits, composed of insoluble amyloid-Beta peptide were hypothesized to be the main etiological factor. “The most important abnormality is an excess of Amyloid-beta peptides brought about through either overproduction or failure in degradation.” (Uzun, Kozumplik, & Folnegović-Smalc, 2011) Later, it was discovered that intracellular neurofibrillary tangles composed of hyper-phosphorylated, helically-paired tau

Due to the inability of the brain to replace nerve cells, some brain function is lost. The key question in Alzheimer’s disease is, what causes the neuron degeneration (Johnson, 1989)? The focus for finding the cause is on abnormal structures found in the brain of people with Alzheimer’s. Unfortunately, the abnormal structures the brain undergoes still has researchers uncertain as to how they are involved in Alzheimer’s and exactly how the disease occurs.

The chaperones have the main role of ensuring proper folding. When a chaperone protein becomes toxic, major changes in the conformation occur as the alpha helix becomes beta pleated sheets. The sheets now expose the hydrophobic amino acid and aggregation, or clumping together of sheets occurs (Borges, 2014).

Alzheimer’s: Scientists know that during Alzheimer’s two abnormal proteins build in the brain. They form clumps called either ‘plaques’ or ‘tangles’. These plaques and tangles interfere with how brain cells work and communicate with each other. The plaques are usually first seen in the area of the brain that makes new memories. A lot of research is focused on finding ways to stop these proteins in their tracks and protect brain cells from harm.

The causes of Alzheimer’s disease are still for the most part unknown. Scientists can’t quite pinpoint the exact causes of Alzheimer’s. But for the last twenty years the cause getting the most attention is that it is caused by an excess amount of insoluble fragments of beta-amyloid, then that leads to the loss of connection between brain cells, then eventually the death of said brain cells. (American Scientist, 44)

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most widespread age-related neurodegenerative diseases. Both diseases impact a considerable number of people, where AD occurs in around 10 percent of the population greater than the age of 65 while PD occurs in roughly 1 percent of the population above the age of 65. AD is considered to be the most widespread cause of dementia, characterised by the progressive memory and cognitive deficits which impair ones day to day activities. The pathological hallmark of AD comprises of extracellular accumulation of senile plaques consisting of mainly amyloid-beta (Aβ) peptides, along with neurofibrillary tangles which are composed of the phosphorylated tau protein, located in the hippocampus and cortex. Conversely, PD is considered to be the most widespread movement disorder that is characterised by symptoms such as rigidity slow movements, resting tremor and other instabilities. The extreme loss of dopaminergic neurones in the substantia nigra is what defines PD, as the loss of this nerve cell can be linked to Lewy bodies containing aggregates of a soluble protein called α-synuclein.

Alzheimer’s disease is named after Dr. Alois Alzheimer who first discovered deviations from normal tissues of healthy individuals in the brain tissue of a lady in 1906. The woman, who showed symptoms of erratic behavior, loss of memory, and problems with communication, died of a then unfamiliar mental disorder. This led Dr. Alzheimer to investigate the cause of her unusual death. He assessed the brain of the woman and found that there were many anomalous masses (amyloid plaques) and intertwined bundles of fiber (neurofibrillary tangles). Scientists today have pinpointed the qualities of Alzheimer’s to be a) tangles in the brain (neurofibrillary tangles), b) plaque in the brain (amyloid plaques), and c) loss of connections among nerve cells.

Alzheimer’s disease or AD is an incurable disorder of the brain that results in loss of normal brain structure and function. In an AD brain, normal brain tissue is slowly replaced by structures called plaques and neurofibrillary tangles. The plaques represent a naturally occurring sticky protein called beta amyloid and in an Alzheimer’s brain, sufferer’s tend to accumulate too much of this protein. Neurofibrillary tangles represent collapsed tau proteins which, in a normal brain along with microtubules, form a skeleton that maintains the shape of the nerve cells. In Alzheimer’s disease, the tau proteins break loose from their normal location and form tangles. Without the support of these molecules, nerve cells collapse and die. As normal

Alzheimer’s Disease is indicated by the break down of the nervous system, essentially the neurons within the brain (MacGill, 2009). The break down leads to nerve cell eradication, and the casualty of tissue throughout the brain (MacGill, 2009). As the disease progress, the brain begins to shrink fiercely, developing loss of its normal functioning (MacGill, 2009). Abnormal protein groups and structures of plaques and tangles characterize the disease (MacGill, 2009). Plagues and tangles are not able to be viewed or tested in the living brain, but are able to be observed in an autopsy of an infected deceased (MacGill, 2009).

DLB main neuropathological structures are Lewy bodies, nevertheless it also has the Alzheimer’s disease (AD) pathology of senile plaques and neurofibrillary tangles (Pervin, Edwards & Lippa, 2016). Astonishing up to 80 percent of individuals can show AD pathology (Colom-Cadena et al., 2013). Lewy bodies are located in cell cytoplasm, spherical in shape, eosinophilic, neuronal attachments, with a compressed hyaline centre and clear halo. They are made of unusual shortened and phosphorylated proteins and alpha-synuclein is the main component (Hancock, 2011). The alpha synuclein accumulations, termed Lewy bodies (LB) and Lewy neuritis (LN), disturb brain chemicals resulting in complications with movement, thinking, mood and behaviour. In a fit brain, alpha-synuclein is essential in brain neurons, especially at presynaptic part, where cell

Chaperones are proteins that ensure the correct folding of the CFTR within the endoplasmic reticulum. Hsp70 is an important cytosolic chaperone that complexes with CFTR and reduces aggregation [5]. The CFTR passes through the endoplasmic reticulum-associated degradation (ERAD) after folding in the ER. This quality control system involves the ubiquitin proteasome system (UPS) for which CFTR is a substrate [16]. If a protein is molded and targeted for degradation, then ubiquitin will covalently attach to lysine residues on the CFTR. Three enzymes are required for the process of ubiquitylation: E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, and E3 ubiquitin protein ligases. E1 enzymes are activated through hydrolysis of ATP, which creates an activated ubiquitin that is transferred to an E2 active site. The activated ubiquitin is then covalently bound to a lysine on the protein by an E3 ligase. A polyubiquitin chain is then formed as ubiquitin molecules link together, and if there are four or more then the misfolded CFTR chain is removed form the ER membrane and targeted for degradation by the 26S proteasome

Under normal condition tau binds to microtubules, stabilizing neuronal structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of the formation of paired helical filaments - neurofibrillary tangles (NFT). The principle components of the senile plaques are neurofibrillary tangles in the cell bodies, neuropil threads, and neurites as well as extracellular A-beta amyloid. These lesions are surrounded by microglial and astrocytes. The brain regions affected by Alzheimer’s disease also contain neuritic or senile plaques in which extracellular deposits of amyloid are surrounded by dystrophic axons as well as the process of astrocytes and microglia. The principle constituent of amyloid is a 4kDa peptide called A-beta amyloid. A-beta amyloid is cleaved from a larger precursor protein called amyloid precursor protein. Similar abnormalities occur in transgenic mice with mutant APP and in individuals with Alzheimer’s

There is a great deal of impetus for understanding the mechanisms that lead to clinical AD and discovering modifiable risk factors. Clinical symptoms of dementia relate to the affected areas of the brain. In AD the symptoms are caused by a progressive loss of cholinergic function due to neuronal cell death in the hippocampus and cerebral cortex, brain regions involved in thought processing and memory. At the microscopic level, the neuropathological hallmarks of AD consists of two kinds of protein aggregates, amyloid plaques and hyper-phosphorylated tangles of tau-protein (Figure 1). Amyloid precursor protein (APP) is a transmembrane protein without known function that is constitutively cleaved

The Gene: Lamin A (LMNA), makes a protein that is required for holding the centre of the nucleus together. When it has been mutated (defect), an abnormal amount of the Lamin A protein called Progerin is produced and makes the cell unstable, this is what influences the diseases aging process.

Proteins play a part in every cellular activity and must fold into proper three dimensional configurations, or native state, to execute their intended functions. Proteomic stressors such as chemical exposure or elevated temperature can inhibit protein folding upsetting protein homeostasis and resulting in cell death and human disease (Broadley 2009). Excessive protein misfolding can lead to amyloid fibrillar aggregates which deposit around brain neurons contributing to the development or progression of neurodegenerative disorders: Alzheimer’s disease, Huntington’s disease and Parkinson’s disease are all fundamentally diseases of protein misfolding (Soto 2003, Hartl 2009).