Review of Amyotrophic Lateral Sclerosis, Parkinson’s and Alzheimer’s diseases helps further define pathology of the novel paradigm for Alzheimer’s with heavy metals as primary disease cause
Introduction
Neurodegenerative diseases with distinctly different clinical presentations share many pathological features at a subcellular level. These dissimilarities often involve disease-specific proteins that are signatures of a disease, for instance, that nevertheless partake in similar subcellular and even systemic events in other disease pathologies.
Cell biology from prokaryote to eukaryote is full of repeated or common systems. Identifying and decoding these repeated models and attempting to overlap them on to pathological pathways of diseases we know less about might help us expand our understanding of the less defined pathology. In this meta-analysis of the literature the pathologies of Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are compared and contrasted to further define and better understand genetic and metabolic similarities as well as highlight how distinct signatures define them from one another. This strategy is applied here to help expand the new AD paradigm that centers on transition metals as a major cause of sporadic AD [1].
At a subcellular level it is clear that processing, trafficking and removal of misfolded or otherwise aberrant proteins play central roles in the pathogenesis of many debilitating neurodegenerative diseases [2], [3], [4]. In AD, for instance, we find misfolded β-amyloid peptide which accumulates in the endoplasmic reticulum (ER) to contribute to ER stress [5]; it is found in the cytosol and plasma and other membranes; with variants even found to partake in transcriptional regulation at a nuclear level [6]. The β-amyloid peptide aggregates extracellularly as amyloid plaque also referred to as neuritic plaques [7]. In addition to these plaques, AD is also characterized by hyperphosphorylated TAU aggregated in the cytosol to form neurofibrillary tangles (NFTs) [8].
Presenilin mutations are linked to early onset familial AD (FAD) [9]. Presenilin 1 and presenilin 2 mutations result in the alteration of β-amyloid peptide processing from amyloid β precursor protein (APP) [10]. These mutations lead to increased and altered γ-secretase enzyme expression to yield abnormally elevated levels of the toxic β-amyloid peptide [11], [12], [13].
Although the neuritic plaques and neurofibrillary tangles are characteristics more commonly associated with AD, PD displays similar pathological features, however, centered on different peptide aberrations. In PD, the α-synuclein gene is at the center of the disease pathology. Mutations can result in a gain-of-function mechanism the outcome of which is an abnormally high cytoplasmic accumulation of α-synuclein forming Lewy bodies [14]. These aggregates can also include ubiquitin and syniphilin-1; proteins involved in facilitation of proteasomal degradation [15].
This indicates an attempt by the preclinical PD cell to eliminate the aberrant α-synuclein via ubiquitination and subsequent proteasomal degradation. However, degradation failure by the proteasome pathway results in oligomer accumulation and the characteristic Lewy body deposits located in the neuron cell bodies, axons and even synapses [10], [16], [8]. Accumulation of the aberrant α-synuclein is thought to contribute to degeneration of dopaminergic neurons [17].
At an intracellular level, oxidation and the related localized inflammation play central roles in the pathology of each AD and PD. Glutathione (GSH) depletion and the associated oxidative stress are shown to be pathological features that induce modifications of TDP-43 [18]. Lewy bodies with TDP-43 inclusions are closely associated with AD, PD and ALS [19]; an aberrant protein that is common to all three diseases. TARDBP (TDP-43) mutation is thought to be a major cause of ALS resulting in a toxic gain-of-function and cytosolic accumulation of the protein which eventually leads to induction of apoptosis [20].
Metal toxicity and the consequential oxidative load will be shown to be a common factor in our comparative study of these three neurodegenerative diseases. Oxidative insults on the α-synuclein peptide, aberrations of which are signatory of PD, are shown to induce its oligomerization. Metal catalyzed oxidation of α-synuclein, in fact, is shown to inhibit filament formation and promote α-synuclein oligomerization via cross-linking [21]. Both AD and PD are characterized by α-synuclein inclusions in senile (amyloid) plaques and Lewy body formations respectively [22].
Both wild type and mutated α-synuclein possess an aggregation propensity [23], [14] and it is proposed herein that the common factor between the two is the oxidation-induced cross-linking that transition metals like copper can catalyze. Rasia et al., for example, show that Cu(II) binds to the α-synuclein peptide at the N-terminus utilizing His-50 as the anchoring amino acid [24]. In AD, as will be demonstrated in greater detail in a hypothetical model, Cu(II) is implicated as a factor that induces β-amyloid peptide aggregation as well [25].
If we look at the AD model with a focus on transition metal involvement we find more evidence to support this oxidative source as a probable starting point or as an upstream facilitator along the disease evolution as outlined in the recently published variation of the newly proposed AD paradigm [1]. Post-mortem investigation of AD brain tissue has revealed elevated mercury levels [26]. Interneuron amyloid plaques of AD and non-AD brains are associated with aluminum, iron, copper and zinc [27], [28]. This presents more evidence indicating a potential catalytic influence by toxic levels of uncontrolled (free) metals in neurological tissue. It also shows these metals to be highly associated with β-amyloid.
Related studies also show that copper level reduction in tissues may contribute directly to lower APP gene expression [29] indicating a correlation between APP demand and free copper. β-Amyloid protein 42 is shown to be a more effective reductant than β-amyloid protein 40; and it is also shown that β-amyloid protein 42 has a higher affinity for metal chelation than 40 [5]. Is β-amyloid protein 42’s known incremental toxicity associated with its greater propensity for metal chelation? These are questions that must be posed and investigated further in new research objectives.
If we go back to PD, one of the main hallmarks of the disease is degeneration of the dopaminergic neurons in the substantia nigra. This is a distinct feature of PD and not the other two, AD or ALS, or of other neurodegenerative diseases for that matter. However, here too, copper as well as iron are implicated in the transformation of the α-synuclein peptide to form aggregates [30], [31], [32], [33], [34].
SOD1 mutations are central to ALS. SOD1 is also a metallo-peptide; an apoprotein that depends on copper and zinc to carry out its antioxidant activity. Magnesium is another metal central to mitochondrial SOD activity. The peptide plays a central role in protection of the cell from oxidative stress [35], [36]. However, this protective feature can shift to a pro-oxidative activity in the case of misfolded SOD1 where the metal is misplaced and may serve as a facilitator of oxidation in this exposed position. In fact, research does support the notion that misfolded SOD1 will induce oxidation rather than serve as a quencher of oxidation [37]. Research also indicates that misfolded SOD1 can induce generation of the hydroxyl radical. It is also shown that the peptide can release its copper so the highly reactive free metal can induce intracellular oxidative damage via the Fenton reaction [38].
Over-expression of SOD1 is shown to protect neurons from oxidative injury due to ischemic events [39]. The antioxidant role of the peptide may inspire an intuitive appreciation for this potential, however, overexpression is also associated with a higher likelihood of SOD1 misfolding [40], [41]. This is likely due to the pro-oxidative state that an unnaturally elevated intracellular SOD1 density might create. SOD1 mutations have also been associated with excito-toxicity [42]. This might be a function of interrupted trafficking and processing of vesicles central to neurotransmitter release and NMDA and AMPA receptor management. It may also be directly associated with inflammatory activity; a pro-oxidative state of SOD1 can spark an oxidative and subsequently, an inflammatory cascade.
It is documented and reported by Bolton et al. that inflammation is shown to have a glutamate-promoting influence on glutamate-regulating enzymes. The dysregulation of the glutamate synthetic enzyme, glutamate synthetase and the glutamate neutralizing enzyme, glutamine dehydrogenase results in over-secreted glutamate and unnaturally extended survival of the AMPA and NMDA agonist (glutamate) to over-stimulate neurons [43] and possibly play a role in apoptosis.
Suppression of mutated SOD1 in motor neurons and glia via virus therapy that encodes shRNA reduces mutated SOD1 transcription [44]. This shows promise as a possible way by which the progressive neurodegenerative effects of SOD1 mutation can be countered. It also sheds light on how the mutation might induce and advance clinical symptoms of ALS. However, if this misfolded SOD1 results in misplacement of the metal to turn this antioxidant molecule into a pro-oxidant, this oxidative overload might be the method by which functional healthy SOD1 is subsequently misfolded as it comes into play to neutralize the misfolded SOD1 with exposed transition metal activity.
If the cell is not able to process the aberrant peptide by way of the Unfolded Protein Response (UPR) or other degradation pathways the pro-oxidative activity can transfer from cell-to-cell. Functional wild type SOD1 can aggregate with misfolded SOD1. The aggregates can also readily exit the cell and enter new ones through macropinocytosis to introduce a pathogenic cycle in healthy cells [45], [46], [47].
This pro-oxidative SOD1 hypothesis may align well with the hypothesis posed here explaining molecular, metabolic and structural events in AD. In particular, this may relate to chelation of metals by the AD β-amyloid peptide as described in previous articles [1]; and briefly summarized in these pages to come.
Section snippets
Metal mismanagement, oxidation, inflammation and apoptosis
Each of the three neurodegenerative diseases presented here – AD, ALS and PD – are proteinopathies characterized by aberrant proteins that are specific and distinct to each of the diseases. However, it must be highlighted as a central point of this review that each protein, β-amyloid, SOD1 and α-synuclein peptides respectively, is intimately associated with metal ion chelation or interaction. Furthermore, it must be noted that these transition metals, copper playing a frequent role, are all
Summary
It has been suggested here that the neuron’s protective counteraction to compounded oxidative stress is, in fact, incremental synthesis of APP and the processing yield from BACE1’s catalytic actions on this protein – various β-amyloid peptide species. The incremental synthesis of APP and β-amyloid peptide resulting from oxidative load are proposed, as part of this new paradigm, to be added redundant and compounding compensatory support to the more common endogenous antioxidants SOD, CAT and
Conflicts of interest statement
The author hypothesis is not inspired by third party influence; financial or other. The proposed paradigm shift and the treatment protocol in this review have not yet been studied in the context of Alzheimer’s disease. A research grant will be pursued from a federal agency in order to avoid conflict of interest.
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