Proteomics Analysis for Therapeutic Options of Neurodegeneration: A Review
Journal of Proteomics & Bioinformatics

Journal of Proteomics & Bioinformatics
Open Access

ISSN: 0974-276X

Review Article - (2017) Volume 10, Issue 5

Proteomics Analysis for Therapeutic Options of Neurodegeneration: A Review

Magdah A Ganash*
Biology Department, King Abdulaziz University, KSA
*Corresponding Author: Magdah A Ganash, Biology Department, Faculty of Science, King Abdulaziz University, KSA, Tel: 00966504598826


Neurodegenerative diseases appear to share numerous common multifactorial degenerative processes that contribute to neuronal death, leading to functional impairments. Therefore researchers hope to understand the mechanisms of Neurodegenerative diseases in order to improve their chances of developing new therapies and strategies that may benefit patients. The Proteomics analysis is one of the strategies that researchers are focusing on in order to tackle such diseases as only through these analyses protein modifications can be characterized and be the targets of drugs that are identified. This review explores the various aspects associated with the neurodegenerative diseases and the recent proteomics analyses that may benefit their treatment. This review also strives to point out the literature hypothesized that oxidative modifications, mitochondrial dysfunction, and impairment of protein degradation execute neuron death. Numerous evidences present in literature raise the possibility the possibility that mitochondria and oxidative stress play a crucial role in neurodegeneration, opening new perspectives for therapy.

Keywords: Neurodegenerative disease; Biomarker; Proteomics; Mass spectrometry


2D-PAGE: Two Dimensional Polyacrylamide Gel Electrophoresis; α: Alpha; β: Beta; γ: Gamma; Aβ: Alpha Beta; AD: Alzheimer's Disease; ALS: Amyotrophic Lateral Sclerosis; ATP: Adenosine Triphosphate; APP: Amyloid beta Precursor Protein; CAG: Cytosine Adenine Guanine (Trinucleotides); CSF: Cerebrospinal Fluid; DJ-1: A Causative Gene for Familial PD and Oncogene; DS: Down Syndrome; EAD: Early Alzheimer's Disease; ESI: Electrospray Ionization; FTD: Frontotemporal Dementia; HTRA2: Mitochondrial Serine Protease; HD: Huntington's Disease; HNE: Protein-bound 4-hydroxy-2-nonenal; IT15: The Huntingtin Gene; LRRK2: Leucinerich Repeat Kinase 2; MALDI-TOF-MS: Matrix-assisted Laser Desorption/Ionization Mass Spectrometry; MNs: Motor Neurons; MS: Mass Spectrometry; MS-MS: Tandem Mass Spectrometry; mtDNA: Mitochondrial DNA; NDD: Neurodegenerative Diseases; NTFs: Intraneuronal Neurofibrillary Tangles; REM: Rapid Eye Movement; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; SOD2: Superoxide Dismutase 2; TDP-43: Transactive Response DNA-binding protein 43; p53: Tumor Protein; PARK2 and PARK6: Causative Genes for Familial PD and an Oncogene; PD: Parkinson's Disease; PKA: Protein Kinase A; PINK1: Putative Kinase 1; POLG: DNA polymerase γ; polyQ: Polyglutamine; PS1and PS2: Presenilin 1 and 2; PTMs: Post-translational Modifications


The characterization and identification of putative disease modifying pathways in neurodegenerative disorders has enormous potential for discovery of new therapeutic agents that target these pathways. There is an increasing evidence that a number of potentially informative Neurodegenerative Disease (NDD) biomarkers can improve the accuracy of diagnosing NDD, especially when they are used as a panel of diagnostic assays and interpreted in the context of neuroimaging and clinical data [1,2]. The greatest contributing risk factor for NDDs is age. With an aging population, the inevitable result is a steep rise in the incidence of NDDs. The first publication that reported about Alzheimer disease (AD) was in 1907, which described a woman in her middle age that had lost her memory with a progressive loss of cognitive functions [3]. James Parkinson in 1817 was the first one who described medically a neurological syndrome and it was known as Parkinson's disease [4]. In 1912, the lewy body that characterized the Parkinson’s disease was reported by Forman et al. [3]. Protein aggregation and inclusion body formation that was mostly associated with many forms of neurodegenerative diseases were detected using different techniques in the last century. These suggested that changes in physicochemical properties of the proteins in human brain were responsible for and lead to neurodegenerative diseases [5].

It is now possible to characterize brain cells, such as neurons and glial cells or even their subcellular components at the molecular level. This ability enables researchers to more closely examine brain cell and their molecular pathways to elucidate distinct brain functions. Proteomics allows the identification of thousands of proteins through descriptive and comparative analyses and can provide a detailed overview of a distinct cellular state. The advent of proteomics has allowed high throughput screening methods to search for biomarkers that could lead to early diagnosis and treatment and to identify changes in the cellular proteome that could provide insight into disease etiology and possible treatments avenues [6]. In neurology and neuroscience, many applications of proteomics have involved neuro-toxicology and neuro-metabolism, as well as the determination of specific proteomic aspects of individual brain areas and body fluids in neurodegeneration. Investigation of brain protein groups in neurodegeneration such as enzymes, cytoskeleton proteins, chaperones, synaptosomal proteins and antioxidant proteins is in progress as phenotype related proteomics [7]. A biomarker is an analyst or a condition of the body that is measurable and is shown to be closely associated with the state of health. Biomarkers for neurodegenerative disorders are essential to facilitate disease diagnosis, ideally at early stages, monitor disease progression, and assess response to existing and future treatments. Biomarkers are broadly divided into three groups: physical measurements or phenotypes such as brain imaging, extracellular beta-amyloid (Aβ) plaque deposition [8]; DNA-based biomarkers [9]; and protein biomarkers [10].

Proteome analysis revealed perturbations in mitochondrial function, free radical production, and neurogenesis that were not observed in p53-deficient neurons. Changes in Tau, cofilin, and other proteins recapitulated abnormalities observed in neurodegenerative states in vivo. Additionally, DNA damage caused a p53-dependent decrease in expression of members of the Protein Kinase A (PKA) signaling pathway. PKA inhibition promoted death in the absence of DNA damage, revealing a novel mechanism by which endogenous down-regulation of PKA signaling may contribute to p53-dependent neuronal death [11]. This review will be vital in harnessing the wealth of existing data on neurodegenerative disease to develop an integrated understanding of its mechanisms and formulate optimal clinical guidelines. This review also focuses on the role of oxidative stress in neurodegenerative diseases. To aid the understanding of toxic targets in neurodegenerative diseases, this review includes characteristics, generation, regulation and physiological functions of Reactive oxygen species with their protein misfolding and aggregations.

Neurodegeneration and Neurodegenerative Diseases

Two words are combining the term “neurodegeneration”, "neuro," referring to nerve cells and "degeneration," referring to progressive damage. This term can be applied to several conditions that result in the loss of nerve structure and function. Kuldip [12] stated that the term neurodegeneration encompasses a broad range of diseases of central and peripheral nervous system. It is only seen in less than 5% of the cases as a clear genetic link have been established, however, majority is sporadic and driven by a combination of genetic and environmental factors. NDD which are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells, primarily affect the neurons in the human brain include Alzheimer's disease (AD), Parkinson's disease (PD) which represents the second most common neurodegenerative diseases after AD, Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and prion diseases. Human NDD range from rare to common illnesses. AD and PD pose serious public health challenges that will increase in the coming decades. Many discoveries have been made in the genetic causes and risk factors for several neurodegenerative diseases [13].

NDD are pathologies affecting body activities and functions (Figure 1) such as movement, balance, respiration and speech. Its incidence is increasing and becoming a threat of converting into a pandemic disease. Pal et al. [14] reported that, there is no treatment for these diseases because the neurons of the central nervous system cannot regenerate on their own after cell death or damage as well all of these diseases involve aggregation of protein or formation of inclusion body due to mutations in genes. The protein aggregation typically consists of fibers containing misfolded protein with a β-sheet conformation, Known as amyloid [5]. Recently, Pal et al. [14] stated that these diseases also cause problems related with movement or mental functioning and commonly characterized by the damage and lose of motor, sensory functions and associated cognitive and behavioral deficits. Numerous NDD were recorded and the most common are:


Figure 1: Symptoms summary of neurodegenerative diseases.

Alzheimer disease

AD is the most prevalent neurodegenerative disease, characterized by the presence of intraneuronal Neurofibrillary Tangles (NTFs) and β-amyloid-containing neurotic plaques as well as the loss of specific populations of neurons [15]. It is characterized by the extracellular deposition of Aβ fibrils and by the intraneuronal accumulation of abnormally phosphorylated tau protein. Preclinical AD can be diagnosed in vivo based on the presence of biomarkers [16,17], or post mortem by the presence of AD-type neuropathological alterations despite no signs of cognitive decline during life. According to Brookmeyer et al. [18] in many cases, Alzheimer may lead to Dementia and is expected to affect one in 85 people in the world by 2050. AD is mostly thought to be a disease in aging, with most diagnosis occurring in those aged 65 years and older [19]. However, early-onset cases do occur and typically arise from genetic causes [17].

Huntington's disease

HD is a devastating autosomal dominant neurodegenerative disease that results from a CAG trinucleotide repeat expansion within the disease-causing huntington/IT15 gene. HD, a neurodegenerative disorder characterized by cognitive and motor degeneration and is caused by an abnormal polyglutamine (polyQ) expansion in the N-terminal part of the huntingtin protein [20]. The clinical symptoms of HD are of progressive involuntary choreatic movements, bradykinesia, cognitive decline and psychiatric syndromes [21]. Impaired olfactory function was noticed in patients and presymptomatic gene carriers [22]. Aggregation of the mutant huntingtin proteins results in neuronal damage in the medium spiny neurons of the neostriatum and other neurons such as in the cortex [23]. Among several mechanisms, a recently suspected toxic mechanism is due to the presence of toxic oligomers [24].

Parkinson’s disease

PD is the second most common progressive neurodegenerative disorder. The neurological lesions are frequently accompanied by cytoplasmic inclusion bodies, termed Lewy bodies, which contains ubiquitin-positive protein aggregates [25]. The prevalence of Lewy bodies in PD has led to a central proposal that aberrant accumulation of protein aggregates is a key contributing factor to the development of Parkinsonism [25]. Loss of DAergic neurons in the substantia nigra of the midbrain and loss of other neurotransmitter phenotype neurons in other brain regions are characteristic neuropathological hallmarks [26]. Prominent clinical features of PD are motor symptoms (bradykinesia, tremor, rigidity and postural instability) and non-motor related PD symptoms (olfactory deficits, autonomic dysfunction, depression, cognitive deficits and sleep disorders). Non-DA brain regions that are affected in PD have recently attracted increasing interest because the onset of the non-motor symptoms linked to these neuropathological alterations are observed early in the course of the disease. They include Rapid Eye Movement (REM) sleep behavior disorder, subtle cognitive deficits, depression, olfactory dysfunction and constipation [27].

Amyotrophic lateral sclerosis

The term Amyotrophic Lateral Sclerosis (ALS) covers a spectrum of neurodegenerative syndromes characterized by progressive degeneration of motor neurons [28]. Rowland and Shneider [29] stated “Lateral sclerosis” which referred to the hardening of the anterior and lateral corticospinal tracts as Motor Neurons (MNs) in these areas degenerate and are replaced by gliosis. ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a progressive, lethal, degenerative disorder of motor neurons. Mulder [30] mentioned that the hallmark of this disease was the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. The paralysis begins focally and disseminates in a pattern that suggests that degeneration is spreading among contiguous pools of motor neurons. One of the earliest symptoms of ALS may be the onset of distal weakness in the arms or legs, a lower motor neuron sign [31]. In the fingers and hands, the weakness presents as the inability to do fine motor movements, and it may be asymmetrical, affecting one arm and the opposite leg. It may also present as a one-sided weakness which then progresses to the opposite side. In contrast to motor weakness, cognitive function and hearing and visual capabilities are spared in the early stages of the disease [31].

Proteomics and neurodegeneration

The term “proteomics” was first introduced in the year 1955. It defines the entire protein complement of a cell line, tissue, or organism. Two definitions of proteomics were recently encountered. The first definition restricts its meaning to the large-scale analysis of gene products to studies involving only proteins [32]. As for the second definition, it combines protein studies with analyses that have a genetic readout such as mRNA analysis, genomics, and the yeast two-hybrid analysis. The proteomics analysis aims at obtaining a more global and integrated view of biology by studying all the proteins of a cell rather than each one individually. Mass spectrometry is considered an essential tool for proteomic analysis for identification and global semi-quantitative measurements of proteins as well as amino acids including protein-protein interaction, protein modifications, protein function, and protein localization studies [33]. Therefore, Verrastro et al. [34] studied and detected the amino acids (Figure 2) by proteomics using Mass Spectrometry. For many years, mass spectrometry has been used for detection and characterization of proteins, and is currently the most useful method for determining oxidative damage of proteins [34].


Figure 2: Amino acids detected by proteomics using mass spectrometry.

The functions of proteomics are summarized as following [35,36]:

1. For the detection, identification, and characterization of the protein component of cells, tissues, and organs at any time point in both healthy and diseased.

2. For creating information related to protein expression levels, post-translational modifications (PTMs) and activity of protein, which plays an important role in understanding the biological system rather than just pure protein identification.

3. For systematic biochemical network analysis, employing mathematical modelling or other system biology tools.

4. For the identification of biomarkers and new targets for drug development.

The main goals of proteomics are to understand the molecular pathogenesis of neurodegenerative disorders, improving treatment efficacy, and enhancing the quality of information. So we need to determine the critical importance of molecular information derived from genomics and proteomics. Recently, proteomics analysis is trying to recognize new biomarkers that can be used for diagnosis and treatment of a specific neurodegenerative disease by using the protein spectrum in the biological material such as Cerebrospinal Fluid (CSF) [32]. Biomarker as a characteristic that is objectively measured and evaluated is an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention [37]. Therefore, biomarkers are powerful tools for assessment of neurodegenerative disorders development and extent of planned therapeutics in the management of the disease [36]. Analysis of CSF is an excellent source for identifying biomarkers for neurological diseases as it can be used in studying the biology of neurodegenerative diseases in living patients, and has been used as a major diagnostic tool for a wide range of conditions affecting both the central and the periphery nervous system [38]. By making a comparison between the protein content of CSF in disease and control groups, proteomics and computational software have emerged as a new and promising model for the discovery of new potential biomarkers, this area of research is however still challenging [33]. There are different proteomics techniques that have been used for the categorization of the human CSF proteome including the following:

1. Two dimensional polyacrylamide gel electrophoresis (2D-PAGE) which separates the proteins according to their charge and molecular weight. The limitation of using 2D-PAGE is that some proteins such as acidic/alkaline and hydrophobic proteins are hard to separate [36].

2. Mass Spectrometry (MS) is providing a useful technique for profiling the peptide or protein constituents of complex mixtures. MS also enables the assessment of qualitative and quantitative differences in protein profiles between different samples. There are many types of MS but the more common ones are Matrix-assisted Laser Desorption/Ionization Mass Spectrometry MALDI-TOF-MS and Electrospray Ionization (ESI) that could be used separately or together [14,33,36]. However, some common proteomic techniques use tandem MS (MS-MS) to analyze the small fragment ions of big ions whose mass was determined in the first MS dimension [36]. The mass spectrometry technique is considered as a sensitive and efficient method for protein identification. Henzel et al. were the first to develop the increased sensitivity of MALDI and demonstrate a fast peptide-mass-fingerprinting method for identifying proteins from two-dimensional gels [39]. The first step in MS technique is digestion of the complex mixture of proteins into small peptides with a protease, usually trypsin, which normally cleaves the protein on the C-terminal side of basic amino acid (lysine and arginine). The next step are separation of the peptides by reverse-phase liquid chromatography (LC) and analyzed by mass spectrometers such as quadrupole/time-of-flight (QTOF), ion trap (IT), orbitrap (OT), or ion cyclotron resonance (ICR) [40].

A proteomic biomarker is defined as ‘a specific peptide/protein that is associated with a specific condition, such as the onset, the manifestation, or progression of a disease or a response to treatment’ [41]. Proteomics biomarker discovery developed over ten years ago in neurodegeneration diseases such as AD, PD, and ALS, but more biomarkers for neurodegenerative disorders identification are needed. Six plasma biomarkers were identified in AD patients by plasma proteomic study using 2D-GE and LC/GC/MS, and one of them is α-1 antitrypsin, which has higher expression level using ELISA in plasma of AD patients [39-42].

Zetterberg et al. [43] have recorded around 30 CSF proteins which have been recognized in two or more proteomics studies as possible biomarkers for AD. In the same line, Korolainen et al. [44] listed 26 proteins which have statistical significant change in AD. 1D-PAGE beside 2D-PAGE with LC-MS/MS was used by Yin et al. [45] to identify a new biomarker in AD and they recognized 21 proteins that had different abundance between AD and controls. Also, 2D-PAGE is used to list other new biomarker for PD [45,46].

Besides using proteomics to discover new biomarkers in neurodegenerative diseases, proteomics are also used to investigate oxidative stress in the brain of patients of neurodegenerative diseases. Protein oxidation, lipid peroxidation (indexed by free or protein-bound 4-hydroxy-2-nonenal (HNE), and DNA and RNA oxidation (indexed by 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine, respectively) are the main oxidative stress in the brain of AD [47]. Castegna et al. [48] used proteomics to determine protein oxidation in AD brain by using immunochemical assay of protein carbonyls coupling with two-dimensional polyacrylamide gel electrophoresis and mass spectrometry analysis. Moreover, Reed et al. [47] used 2D-PAGE and MS to examine lipid peroxidation in the early Alzheimer's disease EAD brain by protein-bound 4-hydroxy-2-nonenal (HNE) comparing to those in control. They have observed 20% increases in HNE-bound proteins in brain of subjects with EAD in contrast to control.

Neurodegenerative diseases causes

Oxidative stress and formation of free radicals/reactive oxygen species, mitochondrial dysfunctions, impaired bioenergetics and DNA damage, neuroinflammatory processes and disruption of cellular/ axonal transport are linked to the formation of toxic forms of NDD-related proteins [49]. There are some proteins that are associated with most of the NDDs such as the microtubule-associated protein tau MAPT which is important for the assembly and stabilisation of microtubules, the Amyloid-β (Aβ), which is derived from the amyloid, the α-Synuclein which belongs to a family of abundant brain proteins, the Prion Protein (PrP), the Transactive response TAR DNA-binding protein 43 TDP-43. NDD-related proteins and their biochemical modifications can be used as biomarkers and may be targeted for the treatment of neurodegenerative diseases [50].

According to Saba et al. [51], there are different causes related to neurodegenerative diseases (Figure 3), most important to be discussed are specified below.


Figure 3: Different factors associated with neurodegenerative disease.

Abnormal protein dynamics with defective protein degradation and aggregation

Pathologically, the main causes of neurodegenerative diseases are the misfolding of the proteins and abnormal protein dynamics with defective protein degradation and aggregation [51], such as aggregation of amyloid-β (Aβ) in AD. The central role of proteins has been translated into biomarker research and also into development of novel therapeutic strategies. Indeed, vaccination against α-synuclein, amyloid-β (Aβ), or tau has been explored, in particular these proteins seem to propagate cell-to-cell and may be accessible to antibodies [52]. Cellular proteins should be maintaining their correct native three-dimensional conformations in order to be biochemically and functionally active. Misfolding, aggregation, and deposition make protein functionally inactive. Uttara et al. [53] showed that the toxicity of Aβ is attributed to histidine residues at position 6, 13 and 14. Those are structural sites for transition of metal ions (Cu2+, Zn2+and Fe3+). According to Ramanan and Saykin [54], PD is characterized by deposition of inclusion bodies (Lewy bodies) of α-synuclein, huntingtin protein in HD, and transactive response DNA-binding protein 43 (TDP-43) in Front Temporal Dementia (FTD) and ALS.

Widespread application of specific antibodies against NDD-related proteins and their modifications led to an explosion of descriptions of new neuropathological phenotypes and enabled the development of reliable diagnostic criteria [55]. Numerous disorders are associated with the degeneration of neurons, including immunological disorders; furthermore, many gene alterations lead to the dysfunction of the encoded proteins. However, not all of these processes associated with microscopically detectable protein depositions, at least not with the currently applied techniques. For example, in hereditary spastic paraplegia, the neuropathological examination, without knowledge of the clinical symptoms, can suggest the condition but there are no specific protein inclusions that allow the observer to link the pathology to a specific gene mutation. Indeed, only few reports describe TDP- 43, tau or crystalloid deposits in hereditary spastic paraplegia [55-57], but their detection is not enough to suggest the gene involved in the development of the disease.

Oxidative stress, free radical formation and mitochondrial dysfunction

Oxidative stress is having too several reactive species for available antioxidants, where oxidative damage is the biomolecular damage caused by attack of reactive species upon the constituents in living organisms [58]. Oxidative stress is a major mechanism by which many neurotoxins act. Animal studies using neurotoxicant-based models to reproduce the key features of neurodegenerative diseases have supported the general role of oxidative stress in neurodegeneration [59]. Free radical formation and protein oxidation in biological conditions represent a pathological event that is associated with many NDDs, such as ALS [60]. As well as the levels of nitrated oxidation proteins have been increased in AD brain and play a significant role in the pathogenesis of AD [56]. Many different reactive and oxidizing species, such as Reactive Oxygen Species (ROS) or reactive nitrogen species (RNS) associated with mitochondrial dysfunction, occur and differ in their reactivity to protein amino acids and sites [61]. Many brain functions were affected by ROS (Figure 4).


Figure 4: ROS effects over brain functions.

Lipid peroxidation, nitrotyrosine, reactive carbonyls, and nucleic acid oxidation are increased in vulnerable neurons of AD patients compared with control, regardless of whether individual neurons contain AD pathology [62]. Thus, signs of oxidative damage precede other pathological events in AD and considered as an early event in the disease pathogenesis [63]. Additionally, patients with prodromal AD, mild cognitive impairment, have increased levels of isoprostanes, which are products of polyunsaturated fatty acid oxidation [63].

Castegna et al. [48] stated that the more amino acidic targets for oxidation and free radicals formation are lysine, histidine, cysteine and methionine; however tyrosine is the generally nitrated amino acid. Many neurodegenerative diseases have an oxidative modification, which leads to oxidative damage to biomolecules, including proteins. Oxidative modification of proteins can have many side effects, such as damage of enzymatic activity, functional alterations, and damage of protein structure, which leads to protein aggregation. However, protein oxidation related neurodegeneration is not only caused by disturbed metal metabolism but also by genetic evidences; suggesting that persons associated with certain types of genetic mutations are more susceptible to neurological pathology compared to those with normal genetic profile [53].

Another major feature of neurodegenerative diseases is mitochondrial dysfunction. According to many researches, mitochondrial dysfunction may be an early or primary event in multiple neurodegenerative diseases. Mitochondrial dysfunction is a putative primary mechanism by which environmental toxicants may induce neurodegeneration [59]. In most of NDD, there are strong signs that explain the early occurrence of mitochondrial dysfunction in disease pathogenesis through the accumulation of mitochondrial DNA (mtDNA) mutations and net production of free oxygen species [64]. The mitochondrial dysfunction could also play a significant role in the pathogenesis of neurodegenerative disorder, and the evidence for mitochondria being a site of damage in these diseases is based in part on observed decrease in the respiratory chain complex activities in PD, AD, and HD [64,65]. Numerous studies [66-68] reported that mitochondrial accumulation of Aβ has been shown in AD patients. There have been several reports of mtDNA mutations in rare maternally inherited pedigrees of Parkinsonism, including the 12SrRNA gene in one family with Parkinsonism, deafness, and neuropathy [69]. More recently, mutations in DNA polymerase γ (POLG), a nuclear-encoded mitochondrial gene and multiple mitochondrial deletions, were reported in Parkinsonism associated with progressive external ophthalmoplegia [70]. The levels of the mitochondrial proteins prohibition, ATP synthase, and Superoxide Dismutase 2 (SOD2) are altered in the substantia nigra and frontal cortex tissue of PD patients compared to controls [71]. Chiasson et al. [72] performed proteomic studies in human brain tissue from PD patients and compared to those from healthy controls showed up-regulation of Peroxiredoxin II, mitochondrial Co-III, ATP synthase D chain, complexin I, profiling, L-type calcium channel d subunit, and fatty-acid binding protein.

Konstanze and Christian [73] indicated that several PD-associated genes interface with pathways regulating mitochondrial function, morphology, and dynamics. In fact, sporadic and familial PD seems to converge at the level of mitochondrial integrity. The mitochondrial complexes I, III, and V are defective in the cerebellar and brain regions of subjects affected by Down Syndrome (DS) [74]. Moreover, reduced mitochondrial redox activity and membrane potentials have been observed in DS astrocytes and neuronal cultures [75]. Exclusively, proteins and their function in main neurodegenerative disorder with mitochondrial dysfunction are shown in Table 1 [64,76-80] and symptoms are shown in Figure 1 [81-83].

Disease Genetic causes Function
Alzheimer's disease APP Amyloid beta precursor protein. Gives rise to A β, the primary component of senile plaques
PS1 and PS2 Presenilin 1 and 2. A component of γ-secretase, which cleaves APP to yield A β
Parkinson's disease α-Synuclein The primary component of Lewy bodies
An ubiquitin E3 ligase activity with an amino-terminal ubiquitin-like domain and a carboxyl-terminal ubiquitin ligase domain
DJ-1 Protects the cell against oxidant-induced cell death
A putative kinase 1 localized to mitochondria. Function unknown. Seems to protect against cell death
LRRK2 A leucine-rich repeat kinase 2. Function unknown
HTRA2 A Mitochondrial serine protease in the mitochondrial intermembrane space. Degrades denatured proteins within mitochondria. Degrades inhibitor of apoptosis proteins and promotes apoptosis if released into the cytosol
Amyotrophic Lateral Sclerosis SOD1 Copper-zinc superoxide dismutase. Converts superoxide to hydrogen peroxide. Disease-causing mutations seem to confer a toxic gain of function
TARDBP The ubiquitin-positive neuronal inclusions protein and encoded by TDP-43.
VCP Valosin-containing protein
Huntington's disease Huntingtin
Function unknown. Disease-associated mutations produce expanded polyglutamine repeats

Table 1: Proteins function in neurodegenerative disorder with mitochondrial dysfunction. Republished and edited from Lin and Beal [64], with permission from right link/ nature publishing group.


Diseases of neurodegenerative are complex, age-related disorders that are a growing health problem, exerting a tremendous burden on affected individuals. Today, more than ever, is an urgent need for new therapies to reverse the progression of these disorders. Up to now, many cellular and molecular events contributing to these disorders have been revealed. Furthermore, increasing evidence implies that mechanisms underlying neuronal demise in these disorders may be shared. As the compromised mitochondria function, misfolding of proteins has also been reported in many disorders. Finally, diagnosis and therapy of complex neurodegenerative diseases requires novel molecular targets. Neurodegenerative disease diagnosis and treatment strategies may need to evolve to reflect a complex genetic architecture. A combination of clinical biomarkers including genotype and blood analysis, brain imaging, and medical history data might be required in order to estimate the effects of multiple pathways.


All the acknowledgment can be referred to King Abdulaziz University.


  1. Clarke R, Smith D, Jobst DM, Refsum H (1998) Folate, vitamin B12, and serum homocysteine levels in confirmed Alzheimer Disease. Arch Neurol 55: 1449-1455.
  2. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368: 387-403.
  3. Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055-1063.
  4. Goetz CG (2011) The history of Parkinson's disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 1: a008862.
  5. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10: S10.
  6. Guillermo M, Noga G, Eran P, Francisca CB (2016) Neurodegeneration and Alzheimer's disease. What can proteomics tell us about the Alzheimer's brain? Mol Cell Proteomics 15: 341-343.
  7. Teruyuki T, Aiko S, Shun S (2016) The Application of Proteomics in Neurology. Current Proteomics 2: 41-53.
  8. Ghidoni R, Paterlini, A, Benussi, L (2013) Translational proteomics in Alzheimer’s disease and related disorders. Clin Biochem 46: 480-486.
  9. Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, et al. (2013) Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical alzheimer disease. Ann Neurol 74: 655-668.
  10. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in alzheimer disease. Nat Rev Neurol 6: 131-144.
  11. Johnson MD, Yu LR, Conrads TP, Kinoshita Y, Uo T, et al. (2004) Proteome analysis of DNA damage-induced neuronal death using high throughput mass spectrometry. J Biol Chem 279: 26685-26697.
  12. Kuldip S (2016) Neurodegeneration Diseases Stem Cell-based therapeutic A perspective. J Neurol Neuroscience 7: 75.
  13. Tsuang DW, Bird TD (2002) Genetics of dementia. Med Clin North Am 86: 591-614.
  14. Pal R, Alves G, Larsen JP, Moller SG (2014) New insight into neurodegeneration: the from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders. Am J Neurodegener Dis 18: 145-175.
  15. Oddo S (2008) The ubiquitin-proteasome system in Alzheimer's disease. J Cell Mol Med. 12: 363-373.
  16. Jack CR, Holtzman DM (2013) Biomarker modeling of Alzheimer’s disease. Neuron 80: 1347-1358.
  17. Jack CR, Wiste HJ, Weigand SD, Rocca WA, Knopman DS, et al. ( 2014) Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: A cross-sectional study. Lancet Neurol 13: 997-1005.
  18. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3: 186-191.
  19. Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88: 1337-1342.
  20. MacDonald ME, Gines S, Gusella JF, Wheeler VC (2003) Huntington's disease. Neuromolecular Med 4:7-20.
  21. Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, et al. (2007) Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS ONE 2: 647.
  22. Li SH, Li XJ (2004) Huntingtin and its role in neuronal degeneration. Neuroscientist 10: 467-475.
  23. Sathasivam K, Lane A, Legleiter J, Warley A, Woodman B, et al. (2010) Identical oligomeric and fibrillar structures captured from the brains of R6 ⁄ 2 and knock-in mouse models of Huntington’s disease. Hum Mol Genet 19: 65-78.
  24. McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW (2002) Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 16: 2136-2148.
  25. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 7: 492-501.
  26. Morris J (2015) Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Diseases: An Overview. The Neurodiagnostic Journal 55: 180-194.
  27. Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344: 1688-1700.
  28. Mulder DW (1982) Clinical limits of amyotrophic lateral sclerosis. Adv Neurol 36: 15-22.
  29. Brashear A, Elovic E (2011) Spasticity: Diagnosis and Management. Demos Medical Publishing, LLC, NY, USA.
  30. Chaurand, P, Sanders ME, Jensen RA, Caprioli RM (2004) Proteomics in Diagnostic Pathology: Profiling and Imaging Proteins Directly in Tissue Sections. The Am J Pathol 165: 1057-1068.
  31. Kroksveen AC, Opsahl JA, Aye TT, Ulvik RJ, Berven FS (2011) Proteomics of human cerebrospinal fluid: discovery and verification of biomarker candidates in neurodegenerative diseases using quantitative proteomics. J Proteomics 74: 371-88.
  32. Verrastro I, Pasha S, Tveen Jensen K, Pitt AR, Spickett CM (2015) Mass Spectrometry-Based Methods for Identifying Oxidized Proteins in Disease: Advances and Challenges. Biomolecules 5: 378-411.
  33. Aggarwal K, Lee KH (2003) Functional genomics and proteomics as a foundation for systems biology. Brief Funct Genomic Proteomic 2: 175-184.
  34. Nayak A, Salt G, Verma SK, Kishore U (2015) Proteomics Approach to Identify Biomarkers in Neurodegenerative Diseases. Int Rev Neurobiol 121: 59-86.
  35. Wagner JA, Williams SA, Webster CJ (2007) Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs. Clin Pharmacol Ther 81:104-107.
  36. Davidsson P, Sjogren M (2005) The use of proteomics in biomarker discovery in neurodegenerative diseases. Dis Markers 21: 81-92.
  37. Henzel WJ, Watanabe C, Stults JT (2003) Protein identification: the origins of peptide mass fingerprinting. J Am Soc Mass Spectrom 14: 931-942.
  38. Pontes AH, de Sousa MV (2016) Mass Spectrometry-based approaches to understand the molecular basis of memory. Front Chem 4: 40.
  39. Mischak H, Allmaier G, Apweiler R, Attwood T, Baumann M, et al. (2010) Recommendations for biomarker identification and qualification in clinical proteomics. Sci Transl Med 2: 46ps2.
  40. Liao PC, Yu L, Kuo CC, Lin C, Kuo YM (2007) Proteomics analysis of plasma for potential biomarkers in the diagnosis of Alzheimer's disease. Proteomics Clin Appl 5: 506-512.
  41. Zetterberg H, Ruetschi U, Portelius E, Brinkmalm G, Andreasson U, et al. (2008) Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand 118: 1-11.
  42. Korolainen MA, Nyman TA, Aittokallio T, Pirttila T (2010) An update on clinical proteomics in Alzheimer's research. J Neurochem 112: 1386-1414.
  43. Yin GN, Lee HW, Cho JY, Suk K (2009) Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res 1265: 158-170.
  44. Guo J, Wang W, Liao P, Lou W, Ji Y, et al. (2009) Identification of serum biomarkers for pancreatic adenocarcinoma by proteomic analysis. Cancer Sci 100: 2292-2301.
  45. Reed TT, Pierce WM, Markesbery WR, Butterfield DA (2009) Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res 1274: 66-76.
  46. Castegna A, Thongboonkerd V, Klein JB, Lynn B, Markesbery WR, et al. (2003) Proteomic identification of nitrated proteins in Alzheimer's disease brain. J Neurochem 85: 1394-401.
  47. Jellinger KA (2010) Basic mechanisms of neurodegeneration: A critical update. J Cell Mol Med 14: 457-487.
  48. Kovacs GG (2014) Current Concepts of Neurodegenerative Diseases. EMJ Neurol 1:78-86.
  49. Saba S, Haque SE, Mir SS (2013) Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions. Journal of Neurodegenerative Diseases 8: 563481.
  50. Valera, E, Spencer B, Masliah E (2016) Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13: 179-189.
  51. Uttara B, Singh AV, Zamboni P, Mahajan R (2009) Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Curr Neuropharmacol 7: 65-74.
  52. Ramanan VK, Saykin AJ (2013) Pathways to neurodegeneration: mechanistic insights role of proteomics. Mol Neurobiol 49: 1181-1199.
  53. Woehrer A, Laszlo L, Finsterer J, Stollberger C, Furtner J, et al. (2012) Novel crystalloid oligodendrogliopathy in hereditary spastic paraplegia. Acta Neuropathol 124: 583-591.
  54. Martinez-Lage M, Molina-Porcel L, Falcone D, McCluskey L, Lee VM, et al. (2012) TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation. Acta Neuropathol 124: 285-291.
  55. Thal DR, Zuchner S, Gierer S, Schulte C, Schols L, et al. (2015) Abnormal Paraplegin Expression in Swollen Neurites, τ- and α-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation. Int J Mol Sci 16: 25050-25066.
  56. Halliwell B, Gutteridge JM (2007) Free Radicals in Biology and Medicine. Oxford University Press, NY, USA.
  57. Jason RC, Timothy JG (2011) The Role of Environmental Exposures in Neurodegeneration and Neurodegenerative Diseases. Toxicol Sci 124: 225-250.
  58. Cookson MR, Shaw PJ (1999) Oxidative stress and motor neurone disease. Brain Pathol 9: 165-186.
  59. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, et al. (1999) Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. Neurosci Lett 269: 52-54.
  60. Castellani RJ, Harris PL, Sayre LM, Fujii J, Taniguchi N, et al. (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31: 175-180.
  61. Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, et al. (2010) Oxidative stress in Alzheimer disease: A possibility for prevention. Neuropharmacology 59: 290-294.
  62. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787-795.
  63. Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, et al. (2005) Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. J Nuerol Sci 233: 145-162.
  64. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, et al. (2005) Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J 19: 2040-2041.
  65. Reddy PH, McWeeney S (2006) Mapping cellular transcriptosomes in autopsied Alzheimer’s disease subjects and relevant animal models. Neurobiol Aging 27: 1060-1077.
  66. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, et al. (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15: 1437-1449.
  67. Thyagarajan D, Bressman S, Bruno C (2000) A novel mitochondrial 12SrRNA point mutation in Parkinsonism, deafness, and neuropathy. Ann Neurol 48:730-736.
  68. Luoma P, Melberg A, Rinne JO (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364: 875-882.
  69. Ferrer I, Perez E, Dalfo E (2007) Abnormal levels of prohibitin and ATP synthase in the substantia nigra and frontal cortex in Parkinson’s disease. Neurosci Lett 415: 205-209.
  70. Chiasson K, Lahaie-Collins V, Bournival J (2006) Oxidative stress and 17-alpha- and 17-beta-estradiol modulate neurofilaments differently. J Mol Neurosci 30: 297-310.
  71. Konstanze FW, Christian H (2010) Mitochondrial dysfunction in Parkinson's disease. Biochimica et Biophysica Acta 1802: 29-44.
  72. Kim S, Vlkolinsky R, Cairns N (2001) The reduction of NADH: ubiquinone oxidoreductase 24-and 75-kDa subunits in brains of patients with Down syndrome and Alzheimer’s disease. Life Sci 68: 2741-2750.
  73. Helguera P, Seiglie J, Rodriguez J (2013) Adaptive downregulation of mitochondrial function in down syndrome. Cell Metab 17: 132-140.
  74. Tang YP, Gershon ES (2003) Genetic studies in Alzheimer’s disease. Dialogues in Clinical Neuroscience 5: 17-26.
  75. Ariga H, Takahashi-Niki K, Kato I, Maita H, Niki T, et al. (2013) Neuroprotective function of DJ-1 in Parkinson's disease. Oxid Med Cell Longev 9: 683920.
  76. Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17: 17-23.
  77. Unal Gulsuner H, Gulsuner S, Mercan FN, Onat OE, Walsh T, et al. (2014) Mitochondrial serine protease HTRA2 p.G399S in a kindred with essentia tremor and Parkinson disease. Proc Natl Acad Sci 111: 18285-18290.
  78. Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin and mitochondrial fidelity in Parkinson’s disease. Neuron 85: 257-273.
  79. Kovacs GG, Budka H (2010) Current concepts of neuropathological diagnostics in practice: neurodegenerative diseases. Clin Neuropathol 29: 271-288.
  80. Korolev IO (2014) Alzheimer’s disease: a clinical and basic science review. Med Student Res J 4: 024-033.
  81. Boschi V, Catricala E, Consonni M, Chesi C, Moro A, et al. (2017) Connected Speech in Neurodegenerative Language Disorders: A Review. Front Psychol 8: 269.
Citation: Ganash MA (2017) Proteomics Analysis for Therapeutic Options of Neurodegeneration: A Review. J Proteomics Bioinform 10:135-143.

Copyright: © 2017 Ganash MA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.