1.
Peculiarities of copper binding to alpha-synuclein.
Source
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. ahmadatt@umich.edu.
Abstract
Heavy metals have been implicated as the causative agents for the pathogenesis of the most prevalent neurodegenerative disease. Various mechanisms have been proposed to explain the toxic effects of metals ranging from metal-induced oxidation of protein to metal-induced changes in the protein conformation. Aggregation of a-synuclein is implicated in Parkinson's disease (PD), and various metals, including copper, constitute a prominent group of alpha-synuclein aggregation enhancers. In this study, we have systematically characterized the a-synuclein-Cu21 binding sites and analyzed the possible role of metal binding in a-synuclein fibrillation using a set of biophysical techniques, such as electron paramagnetic resonance (EPR), electron spin-echo envelope modulation (ESEEM), circular dichroism (CD), and size exclusion chromatography (SEC). Our analyses indicated that a-synuclein possesses at least two binding sites for Cu21. We have been able to locate one of the binding sites in the N-terminal region. Furthermore, based on the EPR studies of model peptides and Beta-synuclein, we concluded that the suspected His residue did not appear to participate in strong Cu21 binding.
Misfolded α-synuclein and toll-like receptors: therapeutic targets for Parkinson's disease.
Source
Department of Neurostience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
Abstract
Parkinson's disease (PD) is typified by the loss of midbrain dopamine neurons, the presence of large proteinaceous α-synuclein-positive intracellular inclusions, oxidatively modified molecules and activated microglia. The etiology of sporadic PD is not fully understood but several lines of evidence suggest that genetic vulnerability and environmental toxicants converge to incite pathology-the multiple hit hypothesis. One gene linked to both familial and sporadic PD is SNCA, which encodes for the protein a-synuclein that has a propensity to misfold into toxic moieties. Here we show that a-synuclein directly activates microglia inciting the production of proinflammatory molecules and altering the expression of Toll-like receptors (TLRs). We discuss the role for α-synuclein-directed TLR expression changes in PD and the therapeutic potential of modifying this response.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Parallel manifestations of neuropathologies in the enteric and central nervous systems.
Source
Department of Human Morphology and Applied Biology, University of Pisa, Italy.
Abstract
BACKGROUND: Neurodegenerative diseases may extend outside the central nervous system (CNS) and involve the gastrointestinal (GI) tract. The gut would appear to be a pathological marker for neurodegeneration, as well as a site for studying the pathophysiology of neurodegeneration. In fact, both in the ENS and CNS, misfolded proteins are likely to initiate a process of neurodegeneration. For example, the very same protein aggregates can be detected both in the ENS and CNS. In both systems, misfolded proteins are likely to share common cell-to-cell diffusion mechanisms, which may occur through a parallel prion-like diffusion process. Independently from the enteric or central origin, misfolded proteins may proceed along the following steps, they: (i) form aggregates; (ii) are expressed on plasma membrane; (iii) are secreted extracellularly; (iv) are glycated to form advanced glycation end-products (AGEs); (v) are internalized through specific receptors placed on neighboring cells (RAGEs); (vi) are cleared by autophagy; and (vii) are neurotoxic. These features are common for a-synuclein (in Parkinson's disease and other synucleinopathies), β-amyloid and tau (in degenerative dementia), SOD-1 and TDP43 (in amyotrophic lateral sclerosis), and PrPsc (in prion diseases). While in some diseases these features are common to both ENS and CNS, in others this remains a working hypothesis. PURPOSE: This review analyzes GI alterations from a pathological perspective to assess whether the enteric nervous system (ENS) mirrors the neuropathology described in the CNS. We discuss the potential mechanisms that lead to the onset and spread of neurodegeneration within the gut, from the gut to the brain, and vice versa.
© 2011 Blackwell Publishing Ltd.
A FRET sensor for non-invasive imaging of amyloid formation in vivo.
Source
Department of Chemical Engineering and Biotechnology, University of Cambridge, Pembroke Street, Cambridge CB2 3RA, UK.
Abstract
Misfolding and aggregation of amyloidogenic polypeptides lie at the root of many neurodegenerative diseases. Whilst protein aggregation can be readily studied in vitro by established biophysical techniques, direct observation of the nature and kinetics of aggregation processes taking place in vivo is much more challenging. We describe here, however, a Förster resonance energy transfer sensor that permits the aggregation kinetics of amyloidogenic proteins to be quantified in living systems by exploiting our observation that amyloid assemblies can act as energy acceptors for variants of fluorescent proteins. The observed lifetime reduction can be attributed to fluorescence energy transfer to intrinsic energy states associated with the growing amyloid species. Indeed, for a-synuclein, a protein whose aggregation is linked to Parkinson's disease, we have used this sensor to follow the kinetics of the self-association reactions taking place in vitro and in vivo and to reveal the nature of the ensuing aggregated species. Experiments were conducted in vitro, in cells in culture and in living Caenorhabditis elegans. For the latter the readout correlates directly with the appearance of a toxic phenotype. The ability to measure the appearance and development of pathogenic amyloid species in a living animal and the ability to relate such data to similar processes observed in vitro provides a powerful new tool in the study of the pathology of the family of misfolding disorders. Our study confirms the importance of the molecular environment in which aggregation reactions take place, highlighting similarities as well as differences between the processes occurring in vitro and in vivo, and their significance for defining the molecular physiology of the diseases with which they are associated.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[Frontier researches for the development of molecular-targeted therapies for familial Parkinson disease].
Source
Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Abstract
Parkinson disease (PD), is a movement disorder pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the inherited forms of PD account for only 5 to 10% of PD cases, the identification of gene mutations in the genes implicated in familial PD in the past 10 years, including the findings regarding the a-synuclein, Parkin, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), PINK1, DJ-1 and the ATP13A2 genes, has advanced understanding of the molecular mechanisms in each case of genetic PD. Most familial forms of PD develop at an early onset. However, recent identification of the leucine-rich repeat kinase (LRRK) 2 gene for a late-onset PD, the clinicopathological feature of which closely resembles that of sporadic PD, is expected to enable the clarification of the underlying causes of general PD. Recent studies on the physiological and pathological functions of these identified gene products have revealed overlapping pathogenetic pathways. The common features of these aberrant pathways are impaired protein degradation/quality control, mitochondrial dysfunction, and altered vesicle transport. Several attempts have been made towards developing molecular-targeted therapies directed against mitochondria (e.g., antioxidants, permeability transition pore modulators, and mitochondrial biogenesis stimulators), protein quality control and vesicle transport (e.g., gene silencing, immunization of asynuclein, and protofibril-destabilizing reagents). To ensure the successful implementation of such strategies, it is important to understand the events occuring at an early stage of PD. Further, studies using mammalian PD models for pharmacological analysis combined with studies employing lower organisms for genetic analyses such as worm, fly, and yeast will be helpful to determine effective prevention and treatment strategies for PD, which will replace the conventional symptomatic treatments for PD.
[Cellular pathophysiology of Parkinson's disease].
Source
Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University, Graduate School of Medicine.
Abstract
To explore pathogenesis of synucleinopathy including Parkinson's disease and multiple system atrophy, we developed cellular model for synucleinopathy. In this experimental model, alpha-synuclein was overexpressed in SH-SY5Y cells, which were then exposed to mitochondrial toxins. The data thus obtained suggested the followings. (1) By the treatment with rotenone, wild type alpha-synuclein overexpressing cells demonstrated intracellular aggregations, which shared a number of features with Lewy bodies. (2) The aggregate formation of alpha-synuclein may be cytoprotective. (3) The catechol-derived quinones are candidate molecules to facilitate the oligomer formation of a-synuclein. (4) The cells overexpressing S129A mutant showed few aggregations. It is suggested that phosphorylation at serine 129 is essential for aggregate formation. (5) In wild-type alpha-synuclein cells treated with rotenone, unfolded protein response (UPR) markers were induced prior to the induction of mitochondrial disruption and caspase-3 activation. (6) On the other hand, the S129A mutant failed to activate these UPRs. Thus it seems plausible that alpha-synuclein toxicity is dependent on the phosphorylation at S129.
[Clinical and pathological study on early diagnosis of Parkinson's disease and dementia with Lewy bodies].
Source
Department of Neurology, Kanto Central Hospital.
Abstract
Cardiac uptake of meta-iodobenzylguanidine (MIBG) is specifically reduced in Lewy body disease (LBD). To see pathological basis of the reduced cardiac uptake of MIBG in LBD, we immunohistichemically examined cardiac tissues from patients with LBD, related movement disorders and Alzheimer's disease (AD). In LBD, cardiac sympathetic denervation occurs, which accounts for the reduced cardiac uptake of MIBG. Patients with LBD have Lewy bodies (LBs) in the nervous system, whereas patients with the other neurodegenerative parkinsonism, parkin-associated Parkinson's disease (PD) and AD and have no LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. We further investigate how a-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. Accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that it heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between alpha-synuclein aggregates and degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.
Mechanisms of neurodegeneration in idiopathic Parkinson's disease.
Source
Department of Neurodegeneration & Restorative Research, Center for Neurological Medicine, University Medical Center Göttingen, Germany. jschulz4@gwdg.de
Abstract
The discovery of mutations in hereditary forms of Parkinson's disease has implicated aggregation of a-synuclein, dysfunction of protein turnover and mitochondrial dysfunction as important mediators in the pathogenesis of Parkinson's disease. Subsequent studies have shown that these factors also represent hallmarks of idiopathic Parkinson's disease. Cell death mechanisms include excitotoxicity, calcium overload, apoptosis and autophagia. Here, I will briefly review the molecular mechanisms of neurodegeneration in Parkinson's disease and point out potential treatment options.
Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology.
Source
Fifth Department of Internal Medicine, Fukuoka University, Fukuoka, Japan.
Abstract
Dementia is relatively common in Parkinson's Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinson's disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.
Golgi apparatus and neurodegenerative diseases.
Source
Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
Abstract
Neurodegenerative disorders are typically characterized by progressive and extensive neuronal loss in specific populations of neurons and brain areas which lead to the observed clinical manifestations. Despite the recent advances in molecular neuroscience, the subcellular bases such as Golgi apparatus (GA) for most neurodegenerative diseases are poorly understood. This review gives a brief overview of the contribution of the neuronal GA in the pathogeneses of neurodegeneration, summarizes what is known of the GA machinery in these diseases, and present the relationship between GA fragmentation and the aggregation and accumulation of misfolded or aberrant proteins including mutant SOD1, a-synuclein, tau, which is considered to be a key event in the pathogenic process, and perturbating in calcium homeostasis, regulation of hormones, lipid metabolism are also linkage to the function of the GA thought to underlie neurodegeneration. Although these precise diseases mechanisms remain to be clarified, more research is needed to better understand how GA function for it and to enable physicians to use this knowledge for the benefit of the patients.
Epidemiology of Parkinson's disease.
Source
Division of Neurology, University of Saskatchewan, Saskatchewan, Canada.
Abstract
The incidence of Parkinson syndrome in North America is 20.5/10(5), adjusted to 1970 US population, and there has been no significant change between 1935 and 1979. The composition of different Parkinson variants in the general population, however, has altered remarkably during recent decades. Arteriosclerotic Parkinsonism is very rarely diagnosed now, post-encephalitic Parkinsonism is extinct and drug induced Parkinsonism, first identified in the 1950s, is now the second most common variant in the combined community and institutionalised population survey. There has been a trend to higher incidence of Parkinson's disease in recent decades and it is predicted that the incidence would rise further if the current population survival trends continue. There is no race or gender difference for the risk of Parkinson's disease. Survival in Parkinson's disease has increased since the widespread use of levodopa. The prevalence rate of Parkinson syndrome in North America is estimated at 300/105. Increased risk of Parkinson's disease in essential tremor patients and the reported protective effect of smoking are artifactual. Twin studies show a concordance rate of 10.5% in monozygotic and 10.8% in dizygotic twins, indicating against a major genetic basis for Parkinson's disease. Several large Parkinson's disease families with autosomal dominant inheritance are well documented. In one such family, linkage to chromosome 4 is reported and mutation in the a-synuclein gene has been identified. In several other families, linkage to that region was not detected. These families are believed to inherit a Parkinson's disease susceptibility trait.
Basic pathologies of neurodegenerative dementias and their relevance for state-of-the-art molecular imaging studies.
Source
Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. a.drzezga@lrz.tu-muenchen.de
Abstract
INTRODUCTION: Rising life-expectancy in the modern society has resulted in a rapidly growing prevalence of dementia, particularly of Alzheimer's disease (AD). Dementia turns into one of the most common age-related disorders with deleterious consequences for the concerned patients and their relatives, as well as worrying effects on the socio-economic systems. These facts justify strengthened scientific efforts to identify the pathologic origin of dementing disorders, to improve diagnosis, and to interfere therapeutically with the disease progression. BASIC PATHOLOGIES: In the recent years, remarkable progress has been made concerning the identification of molecular mechanisms underlying the pathology of neurodegenerative disorders. Growing evidence indicates that a common basis of many neurodegenerative dementias can be found in increased production, misfolding and pathological aggregation of proteins, such as beta-amyloid, tau protein, a-synuclein, or the recently described ubiquitinated TDP-43. This progressive insight in pathological processes is paralleled by the development of new therapeutic approaches. However, the exact contribution or mechanism of different pathologies with regard to the development of disease is not yet sufficiently clear. Considerable overlap of pathologies has been documented in different types of clinically defined dementias post mortem, and it has been difficult to correlate post mortem histopathology data with disease-expression during life. Molecular imaging procedures may play a valuable role to circumvent this limitation. RELEVANCE FOR IMAGING STUDIES: In general, methods of molecular imaging have recently experienced an impressive advance, with numerous new and improved technologies emerging. These exciting tools may play a key role in the future regarding the evaluation of pathomechanisms, preclinical evaluation of new diagnostic procedures in animal models, selection of patients for clinical trials, and therapy monitoring. In this overview, molecular key pathologies, which are currently regarded to be strongly associated with the development of different dementias, will be shortly summarized; it will also be discussed how state-of-the-art imaging technology can assist to visualize these processes now and in the future.
Seed-dependent accelerated fibrillation of alpha-synuclein induced by periodic ultrasonication treatment.
Source
School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul 151-744, Korea.
Abstract
alpha-Synuclein is the major component of Lewy bodies and responsible for the amyloid deposits observed in Parkinson's disease. Ordered filamentous aggregate formation of the natively unfolded a-synuclein was investigated in vitro with the periodic ultrasonication. The ultrasonication induced the fibrillation of a-synuclein, as the random structure gradually converted into a beta-sheet structure. The resulting fibrils obtained at the stationary phase appeared heterogeneous in their size distribution, with the average length and height of 0.28 Mm+/-0.21 Mm and 5.6 nm+/-1.9 nm, respectively. After additional extensive ultrasonication in the absence of monomeric a-synuclein, the equilibrium between the fibril formation and its breakdown shifted to the disintegration of the preexisting fibrils. The resulting fragments served as nucleation centers for the subsequent seed-dependent accelerated fibrillation under a quiescent incubation condition. This self-seeding amplification process depended on the seed formation and subsequent alterations in their properties by the ultrasonication to a state that accretes the monomeric soluble protein more effectively than their reassociation of the seeds back to the original fibrils. Since many neurodegenerative disorders have been considered to be propagated via the seed-dependent amyloidosis, this study would provide a novel aspect of the significance of the seed structure and its properties leading to the accelerated amyloid formation.
NO/cGMP-dependent modulation of synaptic transmission.
Source
Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Strasse, 4, 72076 München, Germany.
Abstract
Nitric oxide (NO) is a multifunctional messenger in the CNS that can signal both in antero- and retrograde directions across synapses. Many effects of NO are mediated through its canonical receptor, the soluble guanylyl cyclase, and the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). An increase of cGMP can also arise independently of NO via activation of membrane-bound particulate guanylyl cyclases by natriuretic peptides. The classical targets of cGMP are cGMP-dependent protein kinases (cGKs), cyclic nucleotide hydrolysing phosphodiesterases, and cyclic nucleotide-gated (CNG) cation channels. The NO/cGMP/cGK signalling cascade has been linked to the modulation of transmitter release and synaptic plasticity by numerous pharmacological and genetic studies. This review focuses on the role of NO as a retrograde messenger in long-term potentiation of transmitter release in the hippocampus. Presynaptic mechanisms of NO/cGMP/cGK signalling will be discussed with recently identified potential downstream components such as CaMKII, the vasodilator-stimulated phosphoprotein, and regulators of G protein signalling. NO has further been suggested to increase transmitter release through presynaptic clustering of a-synuclein. Alternative modes of NO/cGMP signalling resulting in inhibition of transmitter release and long-term depression of synaptic activity will also be addressed, as well as anterograde NO signalling in the cerebellum. Finally, emerging evidence for cGMP signalling through CNG channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels will be discussed.
[Molecular genetics of Parkinson's disease].
Source
Division of Clinical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. The occurrence of PD is largely sporadic, while several families with Mendelian segregation of PD have been reported. PD is thought to be caused by mitochondrial dysfunction, oxidative stress and inflammation based on multiple genetic and environmental factors, resulting in the apoptosis of dopaminergic cells. Six causal genes for Mendelian inherited PD have been identified to date, which indicate the importance of the ubiquitin-proteasome pathway in the molecular pathogenesis of dopaminergic cell death. Recent studies have also indicated the involvement of genetic factors in the pathogenesis of sporadic PD. Many association studies on candidate genes have examined the relationship between PD and polymorphisms; We identified a-synuclein as a definite susceptibility gene for sporadic PD. Since 2001, significant linkage to several loci have been reported in samples of affected sibling pairs. With the recent advances in human genome analyses, genome-wide association studies by SNP chip are being performed to identify susceptibility genes and to establish tailor-made medicine for PD.
Rigid body refinement of protein complexes with long-range distance restraints from pulsed dipolar ESR.
Source
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
Abstract
The modeling of protein-protein complexes greatly benefits from the incorporation of experimental distance restraints. Pulsed dipolar electron spin resonance spectroscopy is one such powerful technique for obtaining long-range distance restraints in protein complexes. Measurements of the dipolar interaction between two spins placed specifically within a protein complex give information about the spin-spin separation distance. We have developed a convenient method to incorporate such long-range distance information in the modeling of protein-protein complexes that is based on rigid body refinement of the protein components with the software Crystallography and NMR System (CNS). Factors affecting convergence such as number of restraints, error allocation scheme, and number and position of spin labeling sites were investigated with real and simulated data. The use of 4 to 5 different labeling sites on each protein component was found to provide sufficient coverage for producing accuracies limited by the uncertainty in the spin-label conformation within the complex. With an asymmetric scheme of allocating this uncertainty, addition of simulated restraints revealed the importance of longer distances within a limited set of total restraints. We present two case studies: (1) refinement of the complex formed between the histidine kinase CheA and its coupling protein CheW, and (2) refinement of intra-helical separations in the protein a-synuclein bound to micelles.
- PMID:
- 17609128
- [PubMed - indexed for MEDLINE]
Lewy body variant of Alzheimer's disease or cerebral type lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem.
Source
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. oyokota1@yahoo.co.jp
Abstract
Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson's disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson's disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer's disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer's disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated alpha-synuclein-positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase-positive nerve fibers were relatively well spared in one case examined compared with Parkinson's disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated a-synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson's disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy-related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy-related pathology.
[Abeta, tau and alpha-synuclein and glial cells].
Source
Tokyo Institute of Psychiatry, Japan. akiyama@prit.go.jp
Abstract
Many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are now characterized by abnormal accumulation of certain proteins in the brain. The key molecules include amyloid beta-protein (Abeta), tau anda-synuclein, all of which are involved in the pathogenesis and provide histopathological hallmarks of the diseases. Abeta is continuously produced in and removed from the brain. Microglia and astrocytes take up and degrade soluble Abeta. In the Alzheimer brain, once-deposited, insoluble Abeta is also removed by phagocytosis by activated microglia. The success of these removal processes, however, is at best partial. The phagocytic removal of insoluble Abeta is associated with neuroinflammation, a potentially neurotoxic reaction. Tau is accumulated in astrocytes under a diversity of pathological conditions in several forms: thorn-shaped astrocytes; tuft-shaped astrocytes; astrocytic plaques. Thorn-shaped astrocytes are associated with gliosis and are not disease-specific. Tuft-shaped astrocytes are characteristic of progressive supranuclear palsy (PSP) and astrocytic plaques of cortico-basal degeneration (CBD). Tau accumulation in oligodendrocytes is referred to as coiled bodies and occurs in PSP, CBD, Pick's disease and some other so-called taupathies. a-Synuclein is accumulated in oligodendrocytes, which is referred to as glial cytoplasmic inclusions (GCI). Occurrence of GCI is diagnostic to multiple system atrophy. Transgenic mouse models in which tau or alpha-synuclein is overexpressed in glial cells indicate that neuronal degeneration occurs following tau/alpha-synuclein accumulation in glial cells, supporting a notion that these abnormal glial cells play pathogenic roles.
- PMID:
- 16637593
- [PubMed - indexed for MEDLINE]
Genetics of Parkinson's disease.
Source
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl
Abstract
The past few years, mutations in 5 genes (a-synuclein, parkin, DJ-1, PINK1, and LRRK2) have been firmly implicated, and additional chromosomal loci have been mapped for inherited forms of Parkinson's disease (PD). These discoveries have profound implications for both the scientific and clinical communities. First, although some of the Mendelian forms of PD are very rare (including those caused by alfa-synuclein, DJ-1, and PINK1 mutations) they are facilitating greatly the dissection of the molecular pathways that lead to death of dopaminergic neurons; these pathways might also be implicated in the pathogenesis of the common forms of PD. Second, the discoveries of Mendelian forms are challenging the concept of PD as one disease, as well as the validity of the current clinico-pathological disease definition. Last, mutations in 2 of these genes turned out to be frequent enough to have relevance in clinical practice: parkin mutations are common in early-onset familial and sporadic PD; moreover, emerging data delineate mutations in the LRRK2 gene (encoding the dardarin protein) as a frequent cause of the familial late onset PD forms, and even of few late-onset sporadic cases. The importance of genetic testing is expected to increase in the near future in the PD field. Here, the author provides a brief update on the genetics of the monogenic forms of PD.
- PMID:
- 16175160
- [PubMed - indexed for MEDLINE]
Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis.
Source
Institut Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Spain. 8082ifa@comb.es
Abstract
Myofibrillar myopathies (MM) are characterized morphologically by the presence of non-hyaline structures corresponding to foci of dissolution of myofibrils, and hyaline lesions composed of aggregates of compacted and degraded myofibrillar elements. Inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare intranuclear inclusions, and by the accumulation of several abnormal proteins. Recent studies have demonstrated impaired proteasomal expression and activity in MM and IBM, thus accounting, in part, for the abnormal protein accumulation in these diseases. The present study examines other factors involved in protein aggregation in MM and IBM. Clusterin is a multiple-function protein which participates in Abeta-amyloid, PrP(res) and a-synucleinaggregation in Alzheimer disease, prionopathies and a-synucleinopathies, respectively. gamma-Tubulin is present in the centrosome and is an intracellular marker of the aggresome. Moderate or strong clusterin immunoreactivity has been found in association with abnormal protein deposits, as revealed by immunohistochemistry, single and double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and in target structures in denervation atrophy. Gamma-Tubulin has also been observed in association with abnormal protein deposits in MM, IBM, and in target fibers in denervation atrophy. These morphological findings are accompanied by increased expression of clusterin and gamma-tubulin in muscle homogenates of MM and IBM cases, as revealed by gel electrophoresis and Western blots. Together, these observations demonstrate involvement of clusterin in protein aggregates, and increased expression of aggresome markers in association with abnormal protein inclusions in MM and IBM and in targets, as crucial events related to the pathogenesis of abnormal protein accumulation and degradation in these muscular diseases
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