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Correlation between Ageing and neurodegeneration. All the cell in the body are affected as we grow old, but it is the neuronal cell which have the highest impact on our survival as we progress towards the older age. These affects are visible as our sensory, motor and cognitive functions declines over time.  It is true that as we enter the sixth decade of our lifespan the chances of us developing neurodegenerative disorder increases and this probability further increases as we enter the seventh and the eight decade of life. The likelihood of developing amyotrophic lateral sclerosis (ALS) rises sharply above the age of 40 years; Parkinson's disease (PD) is very common at the age of 70 and at the same time many people at the age of 85 suffers from Alzheimer's disease (AD). [2-6] There are therefore many evidences (which are still growing in number) telling us about connections between ageing and neurodegenerative diseases.
It is understandable that the nerve cells start to die after a certain age as many of them are non-regenerative cells (after going through a long ageing process) but to say that they are genetically programmed to die is unlikely because we see that many late-onset neurodegenerative disorders are sporadic within families and many humans live to a great age with little or no neurodegenerative loss of any kind. paper
At scientific level, we have made lot of advancements in our understanding of the genetics and pathophysiology of neurodegenerative disorders, but even with these advancements there are many questions still unanswered. One of the main area of research is to find answers about selective neuronal vulnerability (SNV) paper and recent studies have started to shed light upon how cellular and molecular changes which take place during normal ageing, renders the neurons susceptible to degeneration. In other words both environmental factors and disease-specific genetic factors determine the fate of any neuron.
The nerve cells, specifically of our brain, are equally affected by ageing as the other organs of our body. Genetic studies do support the existence of conserved genes playing a part in the ageing of a neuron 14 and they also inform us about the genes that either cause or increase the risk of individual neurodegenerative disease 2-6. This is because these cells tend to experience greater stress and other stress related factors as they grow old. These stresses include stress due to oxidation 7,8, disturbed energy homeostasis 9, increase in the number of damaged proteins 10,11 and abrasions in their nucleic acids 12,13.
Both the genetics and the environmental factors play a crucial role, in which they either counteract or facilitate the central molecular, cellular or both mechanisms of ageing (FIG. 2). For example, as we age, there is a normal increase in the amount of modified lipids, proteins and DNA due to oxidative stress in the brain. The aggregation of A+ in AD, accumulation of Cu/Zn-SOD in motor neurons in ALS and increase in a-synuclein in dopaminergic neurons in PD occur normally during ageing 11,21, but the modifications that increases the vulnerability of the neuronal degeneration in AD, PD, HD or ALS includes specific protein modification like covalent binding of the lipid peroxidation product 4-hydroxynonenal, nitration and carbonylation 2,5,18,19,20. These types of protein aggregates arise partially due to "impaired proteasomal and/or autophagic removal of the (oxidatively) damaged proteins" and various other reasons 10,22. Also alterations that occur during normal ageing in various neurotransmitter and neurotrophic factor signalling pathways are intensified in neurodegenerative disease. For examples reduction of dopamine in substantia nigra neurons in normal ageing and PD 23, decrease in the levels of brain-derived neurotrophic factor (BDNF) in ageing, AD and HD 2,24 etc.
Selective neuronal vulnerability
The question that we now ask is why only selective neurons are affected in a specific type of disease? Why do the neurons of frontal lobe and hippocampal region die in AD whereas the neurons of dentate gyrus granule and interneurons of cortical region are spared? Why do the medium spiny neurons in the striatum die in the case of HD? Why is there a reduction in the lower motor neurons of spinal cord in case of ALS? And why dopaminergic neurons in the substantia nigra die in the case of PD? Once these so called "most vulnerable" neurons are affected in the disease, what factors determine the further neuronal degeneration (for eg of upper motor neurons in ALS and cortical neurons in PD) as the disease progress?
Many recent studies are providing us with information and clues about the factors which determine if a specific neuron will succumbs to or resists an age-related disease. The type of neuron, their physical and molecular characteristics, their function and their location in the neuronal circuitry all collectively play an important role in their doom during ageing 40. In general what we have gathered from these studies is that susceptible neurons are usually large with myelinated axons and cover relatively long distances between regions of nervous system or from peripheral targets to the CNS. Striatal medium spiny neurons, upper and lower motor neurons and the hippocampal and cortical pyramidal neurons that are affected in HD, ALS and AD respectively are example of such kinds 2-6. The reason these studies gives us about the vulnerability of these large projection neurons includes the large cell surface area increasing exposure of cell to toxic environmental conditions including ROS (Reactive Oxigen Species), high energy requirement and dependence on axonal transport (anterograde and retrograde) for continuous function and trophic support.
Though the degeneration of neurons is often restricted to a subpopulations of neurons which have a specific neurotransmitter phenotype (example degeneration of cholinergic motor neurons in ALS, degeneration of GABA [?-aminobutyric acid]-containing striatal neurons in HD and degeneration of dopaminergic neurons in PD), in general it is proved with many evidences that neurons of all the main neurotransmitter phenotypes are endangered by ageing. paper When we see the clinical presentations and the histopathology of AD, PD and ALS, which are caused by genetic mutations causing the onset of the disease earlier (as early as 40 years before then the more common sporadic ones) we see that these mutations affects the similar genetic cascades as the ones affected in the "late onset forms of the similar disease [1-6]. Loss of function and death of neurons unsympathetically affects both the pre- and post-synaptic neurons. It can thus be said that pattern of neuronal degeneration is mostly "domino-like".
Pathways to neuronal death
Apoptosis. Also referred to as programmed cell death (PCD), it plays an essential role in cell development, ageing and diseases like cancer and neurological disorders (Thompson 1995). A common feature in neurological disease is degeneration of neuronal cells and it is now generally accepted that neuronal loss occurs by the untimely activation of apoptotic cell-death pathways. There are two routes involved in these pathways: one involving either the mitochondria (the intrinsic pathway) or the activation of death receptors (the extrinsic pathway). Both these pathways induce the activation of caspases 48 which are the final executioners of cell death. Ultimately, the apoptotic cells is ingested by phagocytes preventing swelling and tissue damage. There are many triggers that have been reported in neuronal apoptosis. Theses includes ROS production, overactivation of glutamate receptors, DNA damage, accumulation of damaged proteins and trophic factor insufficiency 48-51.
Excitotoxicity: Glutamate is amongst the primary excitatory neurotransmitters of the CNS, so much so that most neurons receive synaptic inputs from glutamatergic neurons. Therefore it plays an essential role in synaptic transmission and plasticity that brings about all sensory and motor activities. It is also involved in learning, memory and emotions which comprise the behavioural aspects. The mediating factors of glutamate are cell-surface receptors which flux Na+ and Ca2+ ions. Of these surface receptors, NMDA (N-methyl-d-aspartate) and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) are the most abundant and their excessive activation causes constant Ca2+ influx and ROS production which in turn leads to excitotoxicity damageing dendrites and causing cell death in extreme cases 78.
Ageing brings about molecular and cellular changes that make the neurons vulnerable to excitotoxicity. Impaired ion-motive ATPases, glutamate and glucose transporters cause oxidative and metabolic stress which in turns impair a cell's energy metabolism thus increasing the vulnerability of neurons to excitotoxicity. Also, disease-specific abnormalities increase the adverse effects of glutamate on neurons. Mutant huntingtin, A+, mutant Cu/Zn-SOD, and dopamine all have shown to sensitize neurons to excitotoxic death and studies of mouse models of ALS, PD, AD and HD supports the role for excitotoxicity in these disorders 2-6. Key characteristics that make any neuron particularly prone to excitotoxicity related death includes a high numbers of AMPA and NMDA receptors and low, reduced or mutated calcium-binding proteins. 78
Calcium dysregulation: Under normal resting state of a cell, the concentration of Ca2+ ions in the cytosol is tightly regulated in the range of 75-200nM. This concentration, in response to opening of voltage-dependent Ca2+ and NMDA receptor channels and/or membrane depolarization can increase to 1-10 +M 85. Ca2+ can also be released from inositol-1,4,5-trisphosphate and ryanodine-sensitive stores when the cell is responding to increased cytosolic Ca2+ concentrations or certain extracellular signals. Mitochondria can also sequester Ca2+ and then releasing it into cytosol. Its removal from cytosol is mediated by plasma membrane and endoplasmic reticulum Ca2+-ATPases and Ca2+-binding proteins.
Irregularities in neuronal Ca2+ homeostasis are normal during ageing and have been well documented. Increased Ca2+-dependent hyperpolarizations in hippocampal CA1 neurons and variations in Ca2+-handling characteristics of mitochondria and the ER can be considered as good example 86. Also, continuous increased levels of intracellular Ca2+ has been shown to cause neural degeneration and cell death which is done by activation of proteases and increase of ROS production. Mutations in the genes which cause Huntington disease and familial cases of ALS, AD and PD shows disturbed neuronal Ca2+ homeostasis which in turn contributes to the degeneration of these neurons for example, perturbed Ca2+ regulation in PD and HD has been associated with mutations in a-synuclein and huntingtin respectively 89,90.
Mitochondrial perturbations: Reduction of mitochondrial functionality has been directly associated with cellular ageing in general and neuronal ageing in particular 101. Mitochondrial complex-I activity is reduced during normal ageing but it is siverly impared during in PD 107. In a human clinical study by 102, PET imageing of radiolabelled glucose uptake in brain of participants (age range 20-67 years) showed an age-dependent reduction of glucose metabolism and utilisation in specific regions of brain. Similarities are seen in studies of ageing and neurodegenerative disorders on animal models. Mitochondria isolated from cortical region of the rat brain showed greater ROS production and swelling in response to Ca2+ load in older rats then in younger ones. 110 On the other hand studies by 103-105 on patients with PD, AD and HD showed an extensive reduction in glucose utilisation in the brain region which were severely affected.
Accumulation of damaged molecules: Damaged molecules tend to accumulate in the cells as the age progresses. This fact is widely documented. Increased accumulation of damaged DNA in cells could be because of impaired DNA repair systems 13 where mutations in repair proteins causes early ageing syndromes with neurodegenerative phenotypes 12. Neurons face a typical problem of accumulation of damaged proteins which aggregate as insoluble matter either inside or outside the neuron. This problem is also strongly linked to neurodegenerative disorders. Normally damaged proteins are removed by enzymatic degradation. The three mechanisms by which this is done includes cytosolic proteases, lysosomes and the proteasome. In ageing there are strong evidences that these three are altered in neurons 128-130. Proteasome activity is reduced with the advancing age in rats (in cerebral cortex, hippocampus and spinal cord) 131 and severe malfunction is seen in this system in AD132 and PD133. Similarly there are increasing evidences that shows autophagy is also impaired during ageing and age related disease136.
Protein misfolding: Gain of neurotoxic and loss of protective function in combination.
The etiologies of disease that cause neurodegeneration is highly diverse but still, common pathological factors like formation of abnormal protein conformers and the manifestation of pathognomonic proteinaceous deposits play as a common role in them. Protein misfolding is considered as crucial in the pathogenesis of these disease. Despite the current debate over the role and function of these misfolded proteins, there are increasing evidences that tells us how these harmful proteinaceous species become toxic to cells and how they damage the related and nearby neuronal populations. These evidences not only come from neuropathological studies but also from genetics, animal modeling and biophysical studies. These genetic and animal modeling studies were the key help generators as they were the ones which identified the genes involved in the familial variants of these kinds of diseases. The result of these studies informed us about the two faces of protein misfolding: the gain of toxic function and loss of physiological function, which in many cases occur together. Gnl "The four major neuronal proteins that are prone to aggregation and contribute to neuronal dysfunction and death in neurodegenerative disorders are A+, tau, a-synuclein and huntingtin's Paper. In this review we will consider only PD and related genes.
Parkinson's disease is not as new as many of us think it is. Though it was first formally explained and described in "An assay on the Shaking Palsy" by a London based physician James Parkinson in 1817 web 5, and named not until 1861-62 by Jean-Martin Charcot and Alfred Vulpian (Charcot and Vulpian, 1861, 1862), it has been described in Ayurveda as far back as 5000 B.C. web . In Ayurveda they called it as Kampavata and for its treatment they used a tropical legume called Macuna pruriens called as Atmagupta. This legume is a natural source of L-Dopa web 2. It has since then been described in many other literatures including oldest existing Chinese medical texts web 3 and it is claimed that even the bible (both Old and New testaments) contains references to the symptoms of Parkinson's Disease: "When the guardians of the house tremble, and the strong men are bent" (Ecclesiastes 12 : 3), and the following description in the New Testament "There was a woman who for eighteen years had been crippled by a spirit.....bent and completely incapable of standing erect" (Luke 13:11). web
This specific disorder is the 2nd most common neurodegenerative disorder after Alzheimer's disease. It is an age related disease with a prevalence of 100-200 person per 100,000 humans. 1.4% of the population above the age of 55 and 3.4% above 75 years of age are affected and amongst them it is more prevalent in males (male:female ratio of 1,5-2:1) orphanet Symptoms include resting tremor, rigor and a generalized reduction of locomotor performance. These extrapyramidal symptoms are also (variably) associated with autonomic symptoms like obstipation, erectile dysfunction, sialorrhea; and psychological symptoms like depression, bradyphrenia and dementia. Orphaned though these symptoms respond in a good manner to dopaminergic therapy, complications like dystonia and dyskinesia are mostly observed after 5-10 years of the onset of the disease orphaned
From a broad perspective there are two main clinicopathological aspects involved in PD:
First, there is a clinically defined parkinsonism which comprises the basic features of the Parkinsonian movement disorder (and thus a syndromic term) including resting tremor, bradykinesia, rigidity and postural instability, all problems related to initiation or stopping of movement. Pathologies of these patients correlates to loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc).
Secondly, in postmortem studies, PD is marked by presence of Lewy bodies (LBs) and Lewy neurites in surviving neurons (2). These LBs are intracellular aggregations of lipids and proteins first identified by eosin staining. They are now identified by immunostaining for protein components including ubiquitin and a-synuclein. Therefore pathologically PD requires presence of a-synuclein-positive Lewy pathology in surviving nigral neurons along with nigral cell loss and intact striatal neurons (3).
We can therefore say that PD is a disease with two parts; parkinsonism and Lewy pathology. Though both cannot, on their own specifically define PD, as their occurrence is independent in other neurological settings referred to as synucleinopathies (4) for example in diffuse Lewy body diseases (DLBD) (5). Understanding of these two components is important in order to understand the biochemistry of PD and how the genetic forms of parkinsonism relate to its process. Conveniently, a-synuclein is both part of Lewy pathology and a cause of dominantly inherited disease. bcpd
Majority of all the PD cases are sporadic in nature but about 5-15% of patients belong to a category with a history of this disease in the family. Sadly in these family related cases the onset of the disease is early. The sporadic cases studied suggests the multifactorial etiology which is based upon genetics and mostly environmental factors. At the same time characterization of familial form of PD has allowed us to identify 10 gene loci (PARK1-10) and five disease genes: a-synuclein, ubiquitin-C-terminal hydrolase L1, DJ1, Parkin, and PINK1. Orphaned
a-synuclein: "a protein Chameleon"
One of the pathological hallmark of PD is deposition of aggregated a-synuclein in Lewy bodies and Lewy neuritis. (Figure 1C) This protein is thought to contribute to PD by gain-of-toxic-function effect. When the similar occurs in other neurodegenerative entities it is collectively termed as a-synucleinopathies. a-synuclein is abundantly expressed in the CNS but its physiological function is not very clear. Lng Because it is associated with vesicles and because of its enrichment in presynaptic terminals it is suggested that a-synuclein plays a role in synaptic dynamics as a-synuclein knockout mice have synaptic deficits. bcd
a-Synuclein was first cloned from neuromuscular synapse (electric lobe ) of electric eel Torpedo californica (Maroteaux et al., 1988). Maroteaux L, Campanelli JT, Scheller RH(1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804-2815. 9bcd where it was named after its localization to synapses and nuclei. Since then other homologues have been isolated from many other sources including zebra fish 8. In 1997 a dominant mutation in the a-synuclein gene was identified by Polymeropolous and colleagues in a number of families of Greek or Sicilian ancestry (6)bcd. Physically it has a series of imperfect repeats and includes sequence motif 'KTKEGV' with variable C-terminal tail making it highly acidic and at the same time basally phosphorylated at serine and tyrosine residues. The structural motifs of a-synuclein are shown in fig 1 above. Since there are no detectable secondary structure in solution it is referred to as natively unfolded.
Though it is a natively unfolded protein, it is also addressed as intrinsically disordered protein for it has a considerable conformational plasticity (for reviews, see Volles and Lansbury, 2003; Beyer, 2007; Uversky, 2007). Inside the cell it can be found with different conformations. "In vitro, different a-synuclein conformers can be populated: monomers, which adopt a N-terminal a-helical structure upon membrane binding, morphologically diverse +-sheet rich oligomers called protofibrils, amorphous aggregates and amyloid fibrils with a characteristic cross-b structure." Gnl The central hydrophobic region of a-synuclein which is near the repeats is prone to self-association (23, 24) bcd. Since this region is not present in a-synuclein these homologues vary fundamentally in their tendency to aggregate. In some studies it has been shown that a-synuclein can prevent a-synuclein aggregation in vivo (25) and in vitro (26). Truncated forms of the C-terminal acidic tail type a-synuclein are more prone to aggregation (27, 28)bcd. "-pleated sheet-like bonding stabilizes the aggregated forms. This contrasts with the unstructured protein in solution or folding when bound to lipid, earning a-synuclein the title of "a protein chameleon" (22.
Mutant of a-synuclein and its toxicity:
Many model systems have helped us to understand the toxic effects of a-synuclein (for a review, see Cookson and van der Brug, 2007). These include including Golgi fragmentation (Gosavi et al, 2002), pore formation in cell membrane (Volles et al, 2001; Lashuel et al, 2002), induction of ER stress (Smith et al, 2005; Cooper et al, 2006), removal of anti-apoptotic proteins (Xu et al, 2002) and damage to proteasomal or lysosomal protein degradation (Stefanis et al, 2001; Tanaka et al, 2001; Petrucelli et al, 2002; Snyder et al, 2003; Cuervo et al, 2004; Lindersson et al, 2004).
The first mutation that was discovered in a-synuclein was an A53T point substitution 6bcd. The unusual aspect of this mutation is that in rodent and other species the amino acid is already a threonine 17. A30P and E46K mutations have since been identified in German kinderd 18 and Spanish kinderd 19 respectively. A triplication of the wild type gene is also seen in Iowa kinderd.20 Pathology available from these kinderds confirms a-synuclein "positive Lewy bodies but in many cases not limited to nigra. Many of these patients shows prominent dementia. Spanish E46K mutation is considered as "Lewy body dementia" (19). Glial cell inclusions were found In the Iowa kindred which is characteristic of multiple system atrophy (MSA). Therefore mutations in a-synuclein is widespread and causes "fulminant disease" that may resemble Diffuse Lewy body disease (DLBD). Genomic multiplications along with three a-synuclein missense mutations promotes a-synuclein to aggregate and are hence connected with autosomal dominant PD (Polymeropoulos et al, 1997; Kruger et al, 1998; Singleton et al, 2003; Chartier-Harlin et al, 2004; Farrer et al, 2004; Ibanez et al, 2004; Zarranz et al, 2004).
Heavily insoluble polymers of protein known as fibrils are the end product of a-synuclein aggregation and these fibrillar a-synuclein are thought to be the building block of Lewy bodies. Though Lewy bodies can contain many other proteins including a-synuclein (like cytoskeletal proteins and neurofilaments), fibrils can be produced by a-synuclein alone in-vitro. Immuno-gold labeling by Crowther shows the presence of a-synuclein at sites where Lewy bodies along fibrils were isolated from 29 bcd suggesting that this protein is sufficient to form inclusions [reviewed in (22)]bcd. And since it is the most important marker for Lewy bodies, it shows the importance of a-synuclein in the formation of Lewy bodies 30bcd. Where mutation A53T promoted the formation of fibrils mutation A30P does not, rather it slowed the rate of fibril accumulation while promoting formation of oligomeric species in study byGiasson and Conway (31, 32). In many other studies it has come out that mutations here in a-synuclein promotes formation of oligomeric species instead of fibrils pointing fingers at oligomers for being toxic.
Though a-synuclein is expressed in many tissues, its symptoms are restricted to neuronal cells only. Since protein aggregation is an important aspect of a-synucleinopathies it is important to understand both the genetic and non-genetic factors that increases the rate of the aggregation. Some studies suggests the role of promoter alleles which increases the expression rate of a-synuclein and thus aggregation 42, some suggests that the posttranscriptional modifications of a-synuclein enhances aggregation 44 and many studies have shown how metals, pesticides and oxidizing agents & conditions promotes a-synuclein aggregation. To complicate the mater mentioned till now, a review by Lee et al, 2006 (Lee et al, 2006) tells us how a-synuclein plays a neuroprotective role. According to them transgenic expression of a-synuclein prevents neurodegeneration caused by deletion of a molecular chaperone (cysteine-string protein-a). This chaperon is vitally important in folding and refolding of synaptic SNARE proteins (Chandra et al, 2005)gnl.
It is important to keep in mind that there are many factors playing a part in making the brain vulnerable to these processes making it difficult to reach a conclusive therapy. The first and the fore most is the higher rate of a-synuclein expression in neuronal cells 50 and some neuronal cells are at a higher risk as catechols which includes dopamine, can stabilize oligomeric intermediates of aggregation 53. Also the concentration of macromolecules is higher in the brain which is thought to promote aggregation 51 52. Since the brain uses more than 20% of the body's oxygen intake, there is a reasonably high amount of oxidative stress which it has to undergo. On the other hand point mutations in a-synuclein behave differently; A53T causes damage to spinal cord without nigral cell loss whereas A30P produces no such phenotype63 64.
Despite of our understanding of how the disease progresses and what all elements are involved, we are still unable to either reverse, block or clear a-synuclein from neuronal cells at a clinical level but studies have been done in which peptides acting on the central portion of a-synuclein has shown to prevent aggregation and toxicity 68.