Role of Proteases in the Pathophysiology of Neurodegenerative Diseases

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However, readers should be aware that there are some naturally occurring nonpathogenic amyloid-like fibril formations such as the nanostructure of certain bacteria [ 35 ] and the mammalian melanocyte integral membrane protein [ 36 ]. The pathogenesis of amyloidogenic proteinopathy may be initiated with amyloidogenic peptide fragments by one or more proteases [ 37 ]. Figure 4 illustrates a simplified diagram of APP processing [ 2 ]. These findings may suggest that the metal dyshomeostasis is a critical issue in generation of toxic protein species.

Simplified diagram of APP structure and processing.

The proteasome is a large multisubunit complex that can be analogous to a food waste disposer. The proper function of such system is absolutely necessary for maintaining cell homeostasis [ 41 ]. It is expected that any proteasomal abnormalities may contribute to misfolding and protein aggregation diseases [ 42 , 43 ]. This suggests that proteasome machinery was either malfunctioning or overwhelmed due to massive protein aggregation.


Proteasome activity measurements in human plasma were successfully performed as a useful potential marker for various malignant and nonmalignant diseases [ 44 ]. Amyloid fibril formation that leads to abnormal protein aggregation may result in two functional consequences: i a toxic gain of function and ii a loss of function of the protein in question. Although the mature and organized protein fibrils are usually benign [ 32 , 45 ], it is not well documented how disordered amyloid fibrils are being converted to malfunctioned protein species.

Proteasome activity measurements in plasma.

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Extracellular proteasome activity levels were measured by proteasome 20S assay fluorogenic system Enzo Biochem Inc. The detection of proteolytic activity is based on the release of three fluorogenic peptides. Platelet lysate TDP profile. Insoluble extracellular protein deposits in various human diseases have been recognized for a long time. Many proteins that have a tendency to be misfolded do form aggregates that initiate cellular dysfunction [ 47 ]. This section discusses how the proteins involved in neurodegenerative disease have a tendency to misfold.

If we comprehend the biochemical and biophysical behavior of the proteins and their misfolding features, we will have a better understanding of proteinopathy and relevance to neurodegenerative diseases.

Metalloproteinases and neurodegenerative diseases: pathophysiological and therapeutic perspectives

In the last 25 years or so, many diseases have been linked to protein-misfolding cases, although their etiology of such diseases is different. In this section, the focus will be on neurodegenerative diseases because of the following reasons: i they are progressive, ii early diagnosis for these diseases are not available yet, iii they are not effectively treatable, and iv they inflict enormous personal, societal, and economic burdens. The causes for the initiation of protein aggregation are not well documented; however, oxidative stress-induced reactive oxygen species ROS may be involved due to the role of ROS in several pathological disorders and aging [ 49 , 50 ].

For example, glycine Gly residues are particularly susceptible for loss of a hydrogen ion, which results in the formation of Gly radical on the protein backbone which destabilizes protein structure [ 51 ]. One explanation for a lengthy process would be that the initial nucleation of a misfolded protein is very small and energetically stays in the upper level of the energy landscape see Figure 3. Therefore, the growth of the protein aggregate seed is kinetically unfavorable; hence, recruitment of new aberrant proteins for aggregate formation takes a longer period of time [ 54 , 55 ].

Once the nucleation achieves a critical mass, the fibril formation and subsequent plaque formation become accelerated. This is why clinical manifestation of amyloidoses relevant to neurodegenerative disease mostly appears in old age. Therefore, the lifelong aggregate formation is inevitable in Down syndrome patients, which supports the notion that Down syndrome patients are at high risk in developing AD.

In the USA, it is estimated that more than a quarter million individuals live with Down syndrome and all will develop AD pathology as early as in their 30s [ 56 ]. In summary, protein aggregate formation starts at an early stage of life. This process is quicker in individuals with genetic conditions. Others display clinical signs at an old age as part of aging process. Cellular misfolded proteins are inclined to accumulate in nearby organs, in a preferred cell type in a particular tissue [ 57 ], and in a particular cell organelle [ 58 ].

Although these proteins are distributed in systemic circulation, high concentrations can be maintained in organs. Appearance of signature proteins i. It is interesting to note that misfolded aberrant proteins interact with apoptotic proteins in organ-specific organelle. Pasinelli et al. This observation suggests that misfolded aberrant protein functions are location specific.

Valentine has reviewed studies on mutant SOD1 fragmentation in the Golgi apparatus, which may reveal early molecular signals before the onset of ALS symptoms [ 59 ]. There are more emerging studies in which emphasizing the region-specific protein aggregation can be considered a discriminatory signature in neurodegenerative diseases [ 60 ]. The circulating proteins that have the potential to form extracellular amyloid deposits in multiple organs have been recently reviewed [ 47 ].

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Local production of amyloid and non-amyloid protein species achieves the critical concentration for oligomerization and fibrillogenesis in specific organs. These signature proteins can also be measurable in systemic circulation Table 1. This approach will aid to monitor the progress of aberrant protein aggregation in neurodegenerative diseases. These insoluble protein aggregates tend to accumulate inside the cell; however, ultrastructure analysis of these aggregates may not be the same as that of extracellular amyloid fibrils.

The commonality of these aggregate-forming proteins was discussed earlier Section 1. Therefore, it is reasonably acceptable to classify the aberrant protein aggregation-related neurodegenerative diseases as a special form of amyloidosis [ 47 ]. Protein misfolding and subsequent aggregation are central in neurodegenerative diseases; however, the protein behavior in forming aggregates is somehow disease specific.

In PD, this protein misfolds and accumulates in spherical filamentous structures called Lewy bodies. This encapsulated structure forms particularly in dopaminergic and noradrenergic brainstem neurons and causes premature cell death [ 62 , 63 ]. Therefore, Lewy bodies become a signature pattern for PD. The amyloid cascade hypothesis has been the most studied model of molecular pathogenesis in AD. Not much is known so far. It is clear that the most notable neurodegenerative diseases i. This issue has been recently reviewed, and possibility of targeting TDP as a common therapeutic approach to formulate a treatment for neurodegenerative diseases was discussed [ 72 ].

In our laboratory, we are also working on an assay methodology that uses peripheral blood-derived platelet TDP profile that may help for early diagnosis of such diseases so that early treatment options could be available [ 39 ]. Aging is the normal biological process that includes increased protein misfolding and aggregation process due to either reduced levels of quality control checkpoints such as chaperone system or proteasome complex. The proteins that form orderly amyloid fibers and disorderly amorphous aggregates and plaques show some common and essential biochemical and biophysical features that were discussed earlier.

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Therefore, such age-related neurodegenerative diseases may be considered a special form of amyloidoses [ 47 ]. The biochemical processes in aging are contributing to free radical-induced protein oxidation; hence, unnatural disulfide bridge formations can contribute oxidized protein aggregation as well [ 73 ]. Dismutase metalloenzyme e. This contributes the inefficient removal of reactive oxygen ions; hence, more protein oxidation events take place, and subsequently protein aggregation occurs.

Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration

Principal unanswered questions about these neurodegenerative disorders remain: how preciously native soluble proteins undergo partial unfolding, and does aberrant refolding produce highly stable polypeptide polymers? This publicly available online prediction program www. It is clear that time and supraphysiological concentrations of predictable pro-aggregate proteins are two important parameters in aggregation process.

Other factors such as oxidizable amino acids e. Equilibrium between natively folded protein and aberrant-folded protein can last for a long period of time. Finally, new hydrogen bonds form and stabilize the protein in an insoluble amyloid fibril [ 78 , 79 ]. On the other hand, fibril deposition is not a necessary feature in prion disease.

NMR structure of a domain of prion protein PrR — indicates that mutated amino acids in prion protein are involved in the maintenance of the hydrophobic core [ 80 ]. Exactly, how prion conversion propagates? The disease is currently under study [ 46 ].

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As mentioned in Section 1. The ER protein-folding system is also affected by aging process, and less fold-assisting proteins would be available; hence, unfolded and misfolded protein levels would be expected to be high. Two of the unconventional ER chaperone molecules are calnexin Cnx and calreticulin Crt [ 81 , 82 , 83 ] as cited in [ 84 ]. In a pilot study, we demonstrated that Cnx levels were reduced in aging rat brain as well as in neuronal cell culture Figure 7.

This observation supports the other works published in literature stating that protein-folding mechanisms are less efficient; therefore, aberrant-misfolded proteins rise and form aggregates. Calnexin protein levels in aging. Calnexin protein levels were analyzed by Western blotting. Cnx levels were reduced during the aging process in total brain homogenate, synaptic plasma membrane, and neuronal cell culture.

Dynamic equilibrium between misfolded and natively folded proteins may be shifted in favor of protein misfolding and oligomerization in proteinopathy. No definite amyloid fibrils are seen in diseases, suggesting that smaller diffusible toxic protein species consisting of dimers, trimers, tetramers, and large oligomers may be involved in cell cytotoxicity [ 47 ]. Therefore, forming a plaque or aggregate may be considered a defense mechanism of cell against recruitment of more toxic protein species. The aggregate in plaque no longer poses toxicity for cell life; however, having such foreign structure in the cytosol or in extracellular milieu brings some serious problems in cell homeostasis.

For example, the plaques are insoluble and indestructible by ubiquitinated proteasome system. The increased population of such aggregates may overwhelm or even block the proteasome machinery. Therefore, proteasome either slows down or becomes less functional. Another interference of such toxic protein species is that they nonspecifically bind to receptors and channel proteins on the plasma membrane, thus interfering with numerous cell-signaling events [ 16 , 85 ]. Mitochondrion homeostasis should be taken into consideration as well.

Role of Proteases in the Pathophysiology of Neurodegenerative Diseases Role of Proteases in the Pathophysiology of Neurodegenerative Diseases
Role of Proteases in the Pathophysiology of Neurodegenerative Diseases Role of Proteases in the Pathophysiology of Neurodegenerative Diseases
Role of Proteases in the Pathophysiology of Neurodegenerative Diseases Role of Proteases in the Pathophysiology of Neurodegenerative Diseases
Role of Proteases in the Pathophysiology of Neurodegenerative Diseases Role of Proteases in the Pathophysiology of Neurodegenerative Diseases
Role of Proteases in the Pathophysiology of Neurodegenerative Diseases Role of Proteases in the Pathophysiology of Neurodegenerative Diseases

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