neurodegeneration

• n.

• 神経変性

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/16 00:31:40」(JST)

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Neurodegeneration
Classification and external resources
Para-sagittal MRI of the head in a patient with benign familial macrocephaly.
ICD-10	G30-G32
MeSH	D019636

Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many similarities appear which relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

Links between neurodegenerative disorders

Genetics

Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG encodes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Diseases showing this are known as polyglutamine diseases.

• Polyglutamine: A repeat in this causes dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins. PolyQ studies often use a variety of animal models because there is such a clearly defined trigger – repeat offense. Extensive research has been done using models of worms (C. elegans), fruit flies (Drosophila), mice, and non-human primates. It is important to note that mammalian data is often needed for FDA approval of drugs, so a bulk of the research is done using mice. Using data from the other animals (C. elegans and Drosophila primarily) is often a precursor to finding the equivalent mammalian gene.
  • Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract. Two examples are Huntington's disease and spinocerebellar ataxias. For a complete list see the table under Polyglutamine (PolyQ) Diseases in the article Trinucleotide repeat disorder. While polyglutamine-repeat diseases encompass many different neurodegenerative disorders, there are many more it does not apply to. The genetics behind each disease are different and often unknown.

Protein misfolding

Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins.

• alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease.
• tau: hyperphosphorylated tau protein is the main component of neurofibrillary tangles in Alzheimer's disease.
• beta amyloid: the major component of senile plaques in Alzheimer's disease.

Intracellular mechanisms

Protein degradation pathways

Parkinson’s disease and Huntington’s disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as proteinopathies, and they are primarily caused by aggregates in the following structues:

• cytosol, e.g. Parkinson's & Huntington's
• nucleus, e.g. Spinocerebellar ataxia type 1 (SCA1)
• endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies)
• extracellularly excreted proteins, amyloid-β in Alzheimer’s disease

There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles:

• ubiquitin–proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause proteinopathies including polyQ expansions and alpha-synucleins. Research indicates proteasome enzymes may not be able to correctly cleave these irregular proteins which could possibly result in a more toxic species. This is the primary route cells use to degrade proteins.
  • Decreased proteasome activity is consistent with models in which intracellular protein aggregates form. It is still unknown whether or not these aggregates are a cause or a result of neurodegeneration.

• autophagy–lysosome pathways: a form of programmed cell death (PCD), this becomes the favorable route when a protein is aggregate-prone meaning it is a poor proteasome substrate. This can be split into two forms of autophagy: macroautophagy and chaperone-mediated autophagy (CMA).
  • macroautophagy is involved with nutrient recycling of macromolecules under conditions of starvation, certain apoptotic pathways, and if absent, leads to the formation of ubiquinated inclusions. Experiments in mice with neuronally confined macroautophagy-gene knockouts develop intraneuronal aggregates leading to neurodegeneration.
  • chaperone-mediated autophagy defects may also lead to neurodegeneration. Research has shown that mutant proteins bind to the CMA-pathway receptors on lysosomal membrane and in doing so block their own degradation as well as the degradation of other substrates.

Membrane damage

Damage to the membranes of organelles by monomeric or oligomeric proteins could also contribute to these diseases. Alpha-synuclein can damage membranes by inducing membrane curvature. Extensive tubulation and vesiculation were observed when these proteins were incubated with artificial phospholipid vesicles.

Mitochondrial dysfunction

The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial intermembrane space (IMS). Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. Over production of ROS (oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions.

There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis.

Axonal transport

Axonal swelling and spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria. When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered.

Programmed cell death

Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program. There are, however, situations in which these mediated pathways are artificially stimulated due to injury or disease.

Apoptosis (type I)

Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death.

• Extrinsic apoptotic pathways: Occur when factors outside the cell activate cell surface death receptors (e.g. Fas) which result in the activation of caspases-8 or -10.

• Intrinsic apoptotic pathways: result from mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions both of which lead to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors which can lead the cells down apoptotic pathways.

Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors which in turn cleave other proteins resulting in apoptotic initiation.

Autophagic (type II)

Autophagy is essentially a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Many neurodegenerative diseases show unusual protein aggregates. This could potentially be a result of underlying autophagic defect common to multiple neurodegenerative diseases. It is important to note that this is a hypothesis, and more research must be done.

Cytoplasmic (type III)

The final and least understood PCD mechanism is through non-apoptotic processes. These fall under Type III, or cytoplasmic cell death. Many other forms of PCD are observed but not fully understood or accepted by the scientific community. For example, PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. In addition to this, other cytotoxins that induce PCD at low concentrations act to cause necrosis, or aponecrosis – the combination of apoptosis and necrosis, when in higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.

PCD and neurodegeneration

Current research, often in transgenic animal models, implicates both apoptotic and non-apoptotic pathways in neurodegeneration. Different diseases may enter these pathways at different points, but once triggered can lead to interdependent pathways of cell death. Generally, cell death in neurodegeneration is due to apoptosis and most commonly through the intrinsic mitochondrial pathway.

Neurodegeneration in different disorders

Alzheimer’s disease

Main article: Alzheimer's disease

The following paragraph was taken from the Alzheimer’s disease page.

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.

Alzheimer's disease has been hypothesized to be a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.

Parkinson’s disease

Main article: Parkinson's disease

Parkinson's disease is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. The following paragraph is an excerpt from the Pathophysiology section of the article Parkinson's disease.

The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.

Recent research suggests that impaired axonal transport of alpha-synuclein leads to its accumulation in the Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons. Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.

Huntington’s disease

Main article: Huntington's disease

The following paragraph is an excerpt from the Mechanism section of the article Huntington's disease.

HD causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.

Mutant Huntingtin is an aggregate-prone protein. During the cells' natural clearance process, these proteins are retrogradely transported to the cell body for destruction by lysosomes. It is a possibility that these mutant protein aggregates damage the retrograde transport of important cargoes such as BDNF by damaging molecular motors as well as microtubules.

Amyotrophic lateral sclerosis (ALS)

Main article: Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease) is a disease in which motor neurons are selectively targeted for degeneration. In 1993, missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in subsets of patients with familial ALS. This discovery led researchers to focus on unlocking the mechanisms for SOD1-mediated diseases. Unfortunately, the pathogenic mechanism underlying SOD1 mutant toxicity has yet to be resolved.

Recent independent research by Nagai et al. and Di Giorgio et al. provide in vitro evidence that the primary cellular sites where SOD1 mutations act are located on astrocytes. Astrocytes then cause the toxic effects on the motor neurons. The specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration.

Aging and neurodegeneration

The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging. Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease. One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age.

Therapeutics

The process of neurodegeneration is not well understood so the diseases that stem from it have, as yet, no cures. In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon (Medivation). This drug is in phase III clinical trials for use in Alzheimer’s disease, and also recently finished phase II clinical trials for use in Huntington’s disease.

In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1.

Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.

The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimer's disease, however more research must be done to prove safety and efficacy in humans.

See also

• Category:Neurodegenerative disorders
• Trinucleotide repeat disorders
• Proteopathy
• Nervous system
• Amyloids
• JUNQ and IPOD

References

UpToDate Contents

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• 1. パーキンソン病の病因および発症機序 etiology and pathogenesis of parkinson disease
• 2. パーキンソン病の診断 diagnosis of parkinson disease
• 3. 成人における小脳性運動失調の概要 overview of cerebellar ataxia in adults
• 4. Hereditary spastic paraplegia
• 5. 小児における運動減少性運動障害 bradykinetic movement disorders in children

English Journal

• C9ORF72 repeat expansion not detected in patients with multiple sclerosis.

• Fenoglio C1, De Riz M1, Villa C1, Serpente M1, Ridolfi E1, Bonsi R1, Cioffi SM1, Barone C1, Pietroboni A1, Calvi A1, Scarpini E1, Galimberti D2.Author information 1Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, "Dino Ferrari" Center, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.2Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, "Dino Ferrari" Center, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: daniela.galimberti@unimi.it.AbstractA hexanucleotide repeat expansion in the chromosome 9 Open Reading Frame 72 gene (C9ORF72) has recently been reported to be cause of familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Nevertheless, in the last few years this mutation has been found to be associated with heterogeneous phenotypes, including multiple sclerosis (MS) in concurrence with amyotrophic lateral sclerosis. In this study, we sought to evaluate the presence of the C9ORF72 repeat expansion in a cohort consisting of 314 patients with MS and 222 control subjects. No pathogenic expansion was found in MS and control populations, suggesting that C9ORF72 does not play a major role in MS pathogenesis.
• Neurobiology of aging.Neurobiol Aging.2014 May;35(5):1213.e1-2. doi: 10.1016/j.neurobiolaging.2013.10.096. Epub 2013 Nov 1.
• A hexanucleotide repeat expansion in the chromosome 9 Open Reading Frame 72 gene (C9ORF72) has recently been reported to be cause of familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Nevertheless, in the last few years this mutation has been found to be associated with he
• PMID 24355526

• The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice.

• Martin LJ1, Semenkow S2, Hanaford A2, Wong M3.Author information 1Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: martinl@jhmi.edu.2Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.3Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.AbstractParkinson's disease (PD) is a movement disorder caused by neurodegeneration in neocortex, substantia nigra and brainstem, and synucleinopathy. Some inherited PD is caused by mutations in α-synuclein (αSyn), and inherited and idiopathic PD is associated with mitochondrial perturbations. However, the mechanisms of pathogenesis are unresolved. We characterized a human αSyn transgenic mouse model and tested the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the disease mechanisms. C57BL/6 mice expressing human A53T-mutant αSyn driven by a thymic antigen-1 promoter develop a severe, age-related, fatal movement disorder involving ataxia, rigidity, and postural instability. These mice develop synucleinopathy and neocortical, substantia nigra, and cerebello-rubro-thalamic degeneration involving mitochondriopathy and apoptotic and non-apoptotic neurodegeneration. Interneurons undergo apoptotic degeneration in young mice. Mutant αSyn associated with dysmorphic neuronal mitochondria and bound voltage-dependent anion channels. Genetic ablation of cyclophilin D, an mPTP modulator, delayed disease onset, and extended lifespans of mutant αSyn mice. Thus, mutant αSyn transgenic mice on a C57BL/6 background develop PD-like phenotypes, and the mPTP is involved in their disease mechanisms.
• Neurobiology of aging.Neurobiol Aging.2014 May;35(5):1132-52. doi: 10.1016/j.neurobiolaging.2013.11.008. Epub 2013 Nov 16.
• Parkinson's disease (PD) is a movement disorder caused by neurodegeneration in neocortex, substantia nigra and brainstem, and synucleinopathy. Some inherited PD is caused by mutations in α-synuclein (αSyn), and inherited and idiopathic PD is associated with mitochondrial perturbations. However, th
• PMID 24325796

• Pomegranate juice exacerbates oxidative stress and nigrostriatal degeneration in Parkinson's disease.

• Tapias V1, Cannon JR2, Greenamyre JT3.Author information 1Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA.2School of Health Sciences, Purdue University, West Lafayette, IN, USA.3Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh VA Healthcare System, Pittsburgh, PA, USA. Electronic address: jgreena@pitt.edu.AbstractNumerous factors contribute to the death of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD). Compelling evidence implicates mitochondrial deficiency, oxidative stress, and inflammation as important pathogenic factors in PD. Chronic exposure of rats to rotenone causes a PD-like syndrome, in part by causing oxidative damage and inflammation in substantia nigra. Pomegranate juice (PJ) has the greatest composite antioxidant potency index among beverages, and it has been demonstrated to have protective effects in a transgenic model of Alzheimer's disease. The present study was designed to examine the potential neuroprotective effects of PJ in the rotenone model of PD. Oral administration of PJ did not mitigate or prevent experimental PD but instead increased nigrostriatal terminal depletion, DA neuron loss, the inflammatory response, and caspase activation, thereby heightening neurodegeneration. The mechanisms underlying this effect are uncertain, but the finding that PJ per se enhanced nitrotyrosine, inducible nitric oxide synthase, and activated caspase-3 expression in nigral DA neurons is consistent with its potential pro-oxidant activity.
• Neurobiology of aging.Neurobiol Aging.2014 May;35(5):1162-76. doi: 10.1016/j.neurobiolaging.2013.10.077. Epub 2013 Oct 21.
• Numerous factors contribute to the death of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD). Compelling evidence implicates mitochondrial deficiency, oxidative stress, and inflammation as important pathogenic factors in PD. Chronic exposure of rats to rotenone causes a PD-lik
• PMID 24315037

Japanese Journal

• LABORATORY INVESTIGATION : Renin?angiotensin system involvement in the oxidative stress-induced neurodegeneration of cultured retinal ganglion cells

• Ozawa Yoko,Yuki Kenya,Yamagishi Reiko
• Japanese journal of ophthalmology : the official English-language journal of the Japanese Ophthalmological Society 57(1), 126-132, 2013-01
• NAID 40019546557

• 運動症状発現前のパーキンソン病におけるLewy病変と神経変性

• Tredici Kelly Del,Braak Heiko
• Movement disorders : highlights from the official journal of the Movement Disorder Society 6(2), 8-19, 2012-12
• NAID 40019543184

• 脳内鉄蓄積を伴う神経変性(NBIA)症候群 : 臨床像,組織学的および遺伝学的基礎,治療に関する最新情報

• Schneider Susanne A.,Hardy John,Bhatia Kailash P.
• Movement disorders : highlights from the official journal of the Movement Disorder Society 6(1), 2-14, 2012-07
• NAID 40019416807

Related Links

• Neurodegeneration - ScienceDirect.com

The online version of Neurodegeneration at ScienceDirect.com, the world's leading platform for high quality peer-reviewed full-text journals. ... Help Direct export Export file Format RIS (for EndNote, Reference Manager, ProCite) BibTeX

• Neurodegeneration - National Institute of Neurological ...

General Information for Neurodegeneration ... Neurodegeneration The Neurodegeneration cluster portfolio consists of research on adult onset neurodegenerative diseases of all types, broadly focusing on pathogenesis, treatment and ...

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★リンクテーブル★

リンク元	「神経変性」「nerve degeneration」「neurodegenerative」
拡張検索	「pantothenate kinase-associated neurodegeneration」

「神経変性」

　　[★]

英

neurodegeneration、nerve degeneration、neurodegenerative

関

ニューロン変性

「nerve degeneration」

　　[★]

• 神経変性

関

neurodegeneration、neurodegenerative、neuron degeneration

「neurodegenerative」

　　[★]

• adj.

• 神経変性の

関

nerve degeneration、neurodegeneration

「pantothenate kinase-associated neurodegeneration」

　　[★] パントテン酸キナーゼ関連神経変性症

関

Hallervorden-Spatz disease、Hallervorden-Spatz syndrome