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The immunohistochemical features of dystrophic axons in brain tissues of Papillon dogs with neuroaxonal dystrophy (NAD) were examined in comparison with 1 dog with cerebellar cortical abiotrophy (CCA) and a dog without neurologic signs. Histologically, many dystrophic axons were observed throughout the central nervous system of all dogs with NAD. These axonal changes were absent in the dog with CCA and in the control dog. Severe Purkinje cell loss was found in the dog with CCA, whereas the lesions were milder in all dogs with NAD. Immunohistochemically, the many dystrophic axons were positive for neurofilaments, tau, alpha/beta-synuclein, HSP70, ubiquitin, synaptophysin, syntaxin-1, and synaptosomal-associated protein-25 (SNAP-25). A few dystrophic axons were positive for alpha-synuclein. In addition, these dystrophic axons, especially in the nucleus gracilis, cuneatus, olivaris, and spinal tract of the trigeminal nerve, were intensely immunopositive for the 3 calcium-binding proteins calretinin, calbindin, and parvalbumin. The accumulation of synapse-associated proteins in the dystrophic axons may indicate dysfunction of the synapse at the presynaptic portion. The accumulation of alpha-synuclein in the dystrophic axon and region-specific appearance of calcium-binding protein-positive spheroids are considered as unique features in NAD of Papillon dogs, providing the key to elucidate the pathogenesis.

Human synuclein family consists of alpha-, beta-, and gamma-synucleins. Here, we cloned three genes, sncb, sncga and sncgb from zebrafish. They encode beta-, gamma1-, and gamma2-synucleins, respectively. The zSyn-beta, zSyn-gamma1, and zSyn-gamma2 proteins display 69%, 47%, and 50% identity to human beta-synuclein and gamma-synuclein, respectively. By reverse transcriptase-polymerase chain reaction, we demonstrated that sncb and sncga mRNA were abundant in brain and eye, while sncgb expression was moderate in brain, kidney, ovary and testis. The 1.8-kb 5'-upstream/promoter region of the sncga gene was sufficient to direct green fluorescent protein (GFP) expression in the central nervous system and cranial ganglions. A transgenic line, Tg(sncga:GFP), was generated and its GFP expression is similar to that of endogenous sncga mRNA. Moreover, this line also labels the habenular complex and the domain of GFP expression is larger in the left than in the right habenula. Thus, this line can be used to study sncga gene regulation and for left-right asymmetry study in zebrafish brain., ((c) 2009 Wiley-Liss, Inc.)

Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- > beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder afflicting >500,000 patients in the United States alone. This age-related progressive disorder is typified by invariant loss of dopaminergic substantia nigra neurons (DAN), dystrophic neurites, the presence of alpha-synuclein (SYN) positive intracytoplasmic inclusions (Lewy bodies) in the remaining DAN, and activated microglia. As such, microglial activation and resultant increase in proinflammatory molecules have moved to the forefront of PD research as a potential pathobiologic mechanism of disease. Herein, we present data demonstrating early microglial activation in mice that over-express wild-type SYN, the release of SYN from a SYN overexpressing MN9D cell line, and dose-dependent SYN-mediated activation of primary microglial cultures with consequent increases in proinflammatory molecules. Furthermore, we provide evidence that the CD36 scavenger receptor and downstream kinases are involved in SYN-mediated microglial activation. Together, our data suggest an early role for SYN and inflammation in PD pathogenesis.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by oligodendrocytic cytoplasmic inclusions containing abnormally aggregated alpha-synuclein. This aggregation has been linked to the neurodegeneration observed in MSA. Current MSA treatments are aimed at controlling symptoms rather than tackling the underlying cause of neurodegeneration. This study investigates the ability of the antibiotic rifampicin to reduce alpha-synuclein aggregation and the associated neurodegeneration in a transgenic mouse model of MSA. We report a reduction in monomeric and oligomeric alpha-synuclein and a reduction in phosphorylated alpha-synuclein (S129) upon rifampicin treatment. This reduction in alpha-synuclein aggregation was accompanied by reduced neurodegeneration. On the basis of its anti-aggregenic properties, we conclude that rifampicin may have therapeutic potential for MSA.

The proteasome plays a central role in maintaining cellular homeostasis, in controlling the cell cycle, in removing misfolded proteins that can be toxic, and in regulating the immune system. It is also an important target for novel anticancer drugs, such as bortezomib, a potent inhibitor that has been used successfully in the treatment of multiple myeloma. Here, we show that the antimalaria drug chloroquine inhibits proteasome function in eukaryotic cell extracts and in preparations of purified 20S archaeal proteasome from Thermoplasma acidophilium. Methyl-TROSY-based NMR spectroscopy experiments conducted with the 670 kDa 20S proteasome localize chloroquine binding to regions between the alpha and beta subunits of the alpha-beta-beta-alpha barrel-like structure, approximately 20 A from the proteolytic active sites in this 7-fold symmetric molecule. Complementary amide TROSY experiments that provide further probes of proteasome-inhibitor interactions were performed on a novel 180 kDa single-ring construct containing only alpha subunits, the proper assembly of which was confirmed by electron microscopy. In contrast to the chloroquine-proteasome interaction described here, all previously reported inhibitors of the proteasome, including MG132, bind the catalytic region directly. Consistent with the NMR chemical shift perturbation data reported here that place chloroquine binding distal from sites of proteolysis, we show that MG132 and chloroquine can bind the proteasome simultaneously, further establishing that they exploit two completely separate binding pockets. Our data thus establish a novel class of proteasome inhibitor that functions via a mechanism distinct from binding to active sites.

Since the earliest descriptions of Alzheimer's disease (AD), the presence of senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the typical pathological hallmarks of the disease. Studies over the last twenty years, however, have reported a considerable degree of heterogeneity within the AD phenotype and as a consequence, an overlap between the pathological features of AD not only with normal aging, but also with disorders related to AD. This review discusses: 1) the degree of heterogeneity within AD, 2) the concept of an 'interface' between disorders, 3) the nature and degree of the interface between AD and normal aging, vascular dementia (VD), the tauopathies, synucleinopathies, and prion disease, and 4) whether the original status of AD should be retained or whether AD, normal aging, and the related disorders should be regarded as representing a 'continuum' of neuropathological change.

Dopamine is a potentially toxic neurotransmitter that has long been speculated to contribute to the pathogenesis of Parkinson's disease (PD). Recent work has demonstrated the importance of proper storage of dopamine in vesicles to maintain dopamine homeostasis, thus protecting neurons from the detrimental effects of dopamine accumulation and breakdown in the cytosol. These studies suggest that factors which affect dopamine storage might increase the susceptibility of dopamine neurons to further environmental or genetic insults, exacerbating the neuronal degeneration that characterizes PD. This review seeks to revisit the pathogenicity of cytosolic dopamine and further address the critical role of neurotransmitter storage in dopamine-mediated neurotoxicity.

The manifestation of Lewy bodies (LB) in the brain is a hallmark of Parkinson's disease. Here, we present a comprehensive analysis of protein elements in Lewy bodies by comparative mass spectrometry. Cortical LB inclusions were enriched by sucrose gradient centrifugation from postmortem brains, and a negative control sample was prepared from specimen without LB pathology. Whereas approximately 550 proteins were identified in the LB-enriched sample by mass spectrometry, quantitative comparison with the control sample revealed that approximately 40 proteins were co-enriched with alpha-synuclein, the major component in Lewy bodies. As expected, the list of proteins included previously reported constituents, such as those involved in protein folding, membrane trafficking and oxidative stress. More interestingly, we discovered in the LB-enriched sample several kinases (MAPKK1/MEK1, protein kinase C, and doublecortin-like kinase), a novel deubiquitinating enzyme (otubain 1), and numerous ubiquitin ligases (KPC and SCF). The proteomic studies provide enzyme candidates to investigate the regulation of alpha-synuclein and/or other LB proteins, which may contribute to the formation of Lewy bodies and the toxicity of alpha-synuclein in the related neurodegenerative disorders.

Alzheimer and a number of other neurodegenerative diseases are characterized by the presence of reactive microglia and reactive astrocytes in association with the lesions. The classic view that microglia exist primarily in either a resting or activated state needs to be broadened in view of recent results. Resting microglia are in constant activity sampling their surround. Activated microglia may be pro-inflammatory, releasing inflammatory cytokines and other inflammatory mediators, or anti-inflammatory, promoting the healing process. There is evidence that microglial phagocytosis is more powerful in the anti-inflammatory state. Activated astrocytes also have pro-inflammatory and anti-inflammatory properties. In the pro-inflammatory state they release inflammatory cytokines. In the anti-inflammatory state they release various growth factors. In AD and other neurodegenerative diseases, both microglia and astrocytes are in a pro-inflammatory state. From a therapeutic point of view it is desirable to find methods of tipping the balance towards an anti-inflammatory state for both types of glia.

Mucopolysaccharidoses (MPS) are inherited disorders caused by the deficiency of lysosomal enzymes. Sanfilippo syndrome (MPS III) and Hunter syndrome (MPS II) are characterized by severe and mild neurological disorders, respectively, in which the neurodegenerative mechanisms remain to be clarified. We immunohistochemically examined the involvement of tauopathy/synucleinopathy, cell death and oxidative damage in the brains of three cases each of MPS IIIB and MPS II and age-matched controls. In cases of MPS IIIB, the density of GABAergic interneurons in the cerebral cortex immunoreactive for calbindin-D28K and parvalbumin was markedly reduced when compared with age-matched controls. The swollen neurons showed immunoreactivity for phosphorylated alpha-synuclein but not for phosphorylated tau protein or beta-amyloid protein; those in the cerebral cortex demonstrated nuclear immunoreactivity for TUNEL, single-stranded DNA and 8-OHdG. Neither lipid peroxidation nor protein glycation was marked in MPS cases. The expression levels of superoxide dismutases (Cu/ZnSOD and MnSOD) and glial glutamate transporters (EAAT1 and EAAT2) were reduced in two MPS II cases. The disturbance of GABAergic interneurons can be related to mental disturbance, while synucleinopathy and/or DNA impairment may be implicated in the neurodegeneration of swelling neurons due to storage materials in MPS IIIB cases. These findings suggest the possibility of neuroprotective therapies other than enzyme replacement in MPS patients.

Accumulation of proteins in inclusions in neurological disorders is partly due to dysfunction of the ubiquitin-proteasome system. Proteasomal dysfunction may be caused by misexpression of one or more of its subunits. A large number of antibodies reactive with proteasome subunits were screened on material from patients exhibiting tau- and synucleinopathies. Many antisera against proteasomal subunits (11S activator, 19S regulator ATPase/non-ATPase, and 20S alpha and beta resulted in a distinct nuclear and/or cytoplasmic staining of the entorhinal-hippocampal area and the temporal cortex of Alzheimer's disease (AD) patients. In particular an antibody directed against 19S regulator ATPase subunit 6b (S6b) specifically stained the neurofibrillary tangles and dystrophic neurites in AD, Down syndrome and aged nondemented controls. In other tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy and argyrophilic grain disease), neuronal and/or glial inclusions were also S6b immunoreactive. In contrast, in synucleinopathies (Lewy body disease (LBD) and multiple system atrophy) no S6b staining was seen. Real time quantitative PCR on the temporal cortex of AD patients revealed a significant increase in S6b subunit mRNA. This increase was not found in the gyrus cinguli anterior of patients with LBD. This differential expression of S6b most likely will result in different proteomic patterns. Here we present evidence to show that S6b coexists with a reporter for proteasomal dysfunction (ubiquitin(+1)), and we conclude that S6b transcript up-regulation and the dysfunction in tauopathies may be functionally related.

Dementia is a common, chronic and progressive illness. Many different types of dementia exist. It is important to have knowledge of the various dementia presentations so that the clinician can differentiate one type from another. Past and current approaches of classifying dementias are reviewed in this paper. The past cortical/subcortical scheme is reviewed as well as the current synucleinopathy/tauopathy scheme. This paper focuses on the most common synucleinopathies and tauopathies including Alzheimer's Dementia, Dementia with Lewy Bodies, Parkinson's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy, Multiple System Atrophy and Corticobasal Ganglionic Degeneration. We systematically approach each dementia and review cognitive, psychiatry and neurological features of each. We also compare and contrast each dementia and the synucleinopathies and taupoathies alike. Our goal is to provide the clinician with sufficient knowledge to competently and confidently diagnose a patient who presents with progressive cognitive decline and deterioration in functioning.

Genomic multiplication of the locus-encoding human alpha-synuclein (alpha-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of alpha-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age- and dose-dependent alpha-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting approximately 2% of the population over 65 years of age.

The accumulation of mutant aggregate-prone proteins is a feature of several human disorders, collectively referred to as protein conformation disorders or proteinopathies. We have shown that autophagy, a cytosolic, non-specific bulk degradation system, is an important clearance route for many cytosolic toxic, aggregate-prone proteins, like mutant huntingtin and mutant alpha-synucleins. Induction of autophagy enhances the clearance of both soluble and aggregated forms of the mutant protein, and protects against toxicity caused by these mutations in cell, fly, and mouse models. Inhibition of autophagy has opposite effects. Thus, the autophagic pathway may represent a possible therapeutic target in the treatment of certain protein conformation disorders.

A number of the lysosomal storage diseases that have now been characterized are associated with intra-lysosomal accumulation of lipids, caused by defective lysosomal enzymes. We have previously reported neuronal accumulation of both alpha- and beta-synucleins in brain tissue of a GM2 gangliosidosis mouse model. Although alpha-synuclein has been implicated in several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, its functions remain largely unclear. In our present study, we have examined a cohort of human lipidosis cases, including Sandhoff disease, Tay-Sachs disease, metachromatic leukodystrophy, beta-galactosialidosis and adrenoleukodystrophy, for the expression of alpha- and beta-synucleins and the associated lipid storage levels. The accumulation of alpha-synuclein was found in brain tissue in not only cases of lysosomal storage diseases, but also in instances of adrenoleukodystrophy, which is a peroxisomal disease. alpha-synuclein was detected in both neurons and glial cells of patients with these two disorders, although its distribution was found to be disease-dependent. In addition, alpha-synuclein-positive neurons were also found to be NeuN-positive, whereas NeuN-negative neurons did not show any accumulation of this protein. By comparison, the accumulation of beta-synuclein was detectable only in the pons of Sandhoff disease cases. This differential accumulation of alpha- and beta-synucleins in human lipidoses may be related to functional differences between these two proteins. In addition, the accumulation of alpha-synuclein may also be a condition that is common to lysosomal storage diseases and adrenoleukodystrophies that show an enhanced expression of this protein upon the elevation of stored lipids.

The human synuclein protein family includes alpha-synuclein, which has been linked to both familial and sporadic Parkinson's disease, and the highly homologous beta and gamma-synuclein. Mutations in alpha-synuclein cause autosomal dominant early onset Parkinson's, and the protein is found deposited in a fibrillar form in hereditary and idiopathic forms of the disease. No genetic link between beta and gamma-synuclein, and any neurodegenerative disease has been established, and it is generally considered that these proteins are not highly pathogenic. In addition, beta and gamma-synuclein are reported to aggregate less readily than alpha-synuclein in vitro. Indeed, beta-synuclein has been reported to protect against alpha-synuclein aggregation in vitro, as well as alpha-synuclein-mediated toxicity in vivo. Earlier, we compared the structural properties of the highly helical states adopted by all three synucleins in association with detergent micelles in an attempt to delineate the basis for functional differences between the three proteins. Here, we report a comparison of the structural and dynamic properties of the free states of all three proteins in order to shed light on differences that may help to explain their different propensities to aggregate, which in turn may underlie their differing contributions to the etiology of Parkinson's disease. We find that gamma-synuclein closely resembles alpha-synuclein in its free-state residual secondary structure, consistent with the more similar propensities of the two proteins to aggregate in vitro. beta-Synuclein, however, differs significantly from alpha-synuclein, exhibiting a lower predisposition towards helical structure in the second half of its lipid-binding domain, and a higher preference for extended structures in its C-terminal tail. Both beta and gamma-synuclein show less extensive transient long-range structure than that observed in alpha-synuclein. These results raise questions regarding the role of secondary structure propensities and transient long-range contacts in directing synuclein aggregation reactions.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized by the formation and intraneuronal accumulation of fibrillar aggregates of alpha-synuclein (alpha-syn) protein in affected brain regions. alpha-Syn has biochemical properties and a structural motif characteristic of fatty acid binding proteins. Using the fatty acid binding resin Lipidex-1000, we investigated the capture of alpha-, beta-, and gamma-syn proteins as lipid-associated proteins from normal and DLB brain lysates, and from normal human cerebrospinal fluid (CSF). These were eluted from Lipidex-1000 and analyzed by SDS-NuPAGE followed by Western blotting. Using this methodology, we have been able to extract full-length and truncated forms of alpha-syn from brain lysates. We also extracted low levels of beta-syn from DLB brains, but failed to extract any gamma-syn. We were able to capture only full-length monomeric alpha-syn from normal human CSF. Our data confirm the fatty acid binding properties of alpha-syn, and to a lesser extent beta-syn, but suggest that gamma-syn does not share this same characteristic.

Several epidemiological studies have suggested a role for environmental pesticide exposures in idiopathic Parkinson's disease. The purpose of this study was to test the hypothesis that exposure to pesticides such as endosulfan and/or zineb during critical periods of postnatal development could result in neuronal dysfunction and enhance the impact of these pesticides during exposure as adults. C57BL/6 mice, exposed daily to each of the pesticides or their mixtures from postnatal days 5 to 19, exhibited insignificant changes in striatal dopamine, acetylcholinesterase and alpha-synuclein levels. However, mice exposed to these pesticides as juveniles and re-exposed at 8 months of age had significantly altered striatum and brain cortex neurotransmitter levels. Thus, mice re-exposed during adulthood to zineb, endosulfan and their mixtures showed a significantly depleted striatal dopamine levels, to 22, 16 and 35% of control, respectively. Acetylcholinesterase activity in the cerebral cortex was significantly increased in all pesticide treated groups (rho< or =0.05) upon repeated exposure, and pesticide mixture treatment also significantly increased levels of normal and aggregated alpha-synuclein. Collectively, these findings support our hypothesis that exposure to pesticides such as endosulfan and zineb during critical periods of postnatal development contributes to neurotransmitter changes upon re-challenge in adulthood.

Previous studies have shown that beta-synuclein (beta-syn), the homologue of alpha-syn, inhibited alpha-syn aggregation and stabilized Akt cell survival signaling molecule, suggesting that beta-syn was protective against alpha-syn-related neurodegenerative disorders, such as Parkinson's disease and diffuse Lewy body disease. However, emerging evidence argues that the situation may be not so simple. Two missense mutations of beta-syn were identified in familial and sporadic diffuse Lewy body disease, and wild type beta-syn was induced to form fibril structures in vitro, while, alpha-syn was shown to be protective against neurodegeneration caused by deletion of cysteine-string protein-alpha, the presynaptic cochaperone to Hsc70 in mice. Collectively, alpha- and beta-syn are both, but in varying degrees, featured with two opposite properties, namely normal chaperone and anti-chaperone. By reviewing recent progress in syn biology with a particular focus on beta-syn, this manuscript refers to the intriguing possibility that the dual syn proteins might have acquired a driving force for synaptic evolution. Hypothetically, the anti-chaperone syn may provoke stress-induced diverse responses, whereas, the chaperone syn may provide buffering for them, allowing accumulation of nonlethal phenotypic variations in synapses. Consequently, dual syn proteins may cope with forthcoming stresses in the brain by stimulating adaptive evolution. In this context, failure to regulate this process due to various causes, such as gene mutations and environmental risk factors, may result in imperfect adaptability against stresses, leading to neurodegenerative disorders.

Study Objective: To determine the frequency of rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia among patients with Alzheimer disease and control subjects., Design: Overnight polysomnography., Settings: Sleep laboratory., Patients: Fifteen patients with probable Alzheimer disease (mean age +/-SD, 70.2+/-5.6) and 15 age-matched healthy control subjects (mean age +/- SD, 67.9 +/-5.4)., Intervention: N/A., Results: Four patients with Alzheimer disease presented REM sleep with-out atonia. One of these patients had all the polysomnographic features of RBD, including behavioral manifestations during REM sleep., Conclusion: RBD is rare, but REM sleep without atonia is relatively fre-quent in patients with probable Alzheimer disease, a tauopathy.

The aetiology of idiopathic Parkinson's disease (PD) is poorly defined but environmental aggression may be relevant. Here, we report a new model of PD in mice, based on chronic inoculation with neurotoxins in the nasal cavity, which is a natural route of contact with the environment. C57BL/6 mice, submitted to daily intranasal inoculation with MPTP for 30 days, developed motor deficits that correlated with a progressive and severe depletion of striatal dopamine levels, and loss of tyrosine hydroxylase and dopamine transporter staining in substantia nigra and striatum. Moreover, mice intranasally inoculated with MPTP developed strong astrogliosis and microgliosis in substantia nigra and striatum. Consistent with these observations, a role for oxidant aggression was demonstrated by increased levels of Mn-superoxide dismutase. However, alpha-synuclein aggregation was not observed. This new animal model provides a new tool for studying PD symptoms that develop slowly over time, and it may be used to asses risk from environmental neurotoxins.

The synucleinopathies are neurodegenerative disorders defined by inclusions composed of aberrantly fibrillized alpha-synuclein, but factors contributing to this process remain largely unknown. The authors examined the glucocerebrosidase gene in 75 autopsy specimens with different synucleinopathies and identified mutations in 23% of cases of dementia with Lewy bodies, expanding on previous findings in subjects with Parkinson disease. Mutations in this lysosomal protein may interfere with the clearance or promote aggregation of alpha-synuclein.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies (LBs) are detected in approximately 10% of PSP cases, but there is little information on the relationship of LBs to tau pathology. We determined the frequency of LBs in a large series of autopsy-confirmed cases of PSP and studied the density and distribution of LBs, including Parkinson disease stage, in cases with LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including assessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for alpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple system atrophy in addition to PSP and was excluded from further study along with 2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were compared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, Braak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile plaques were not different among PSP, LBD, and PSP/LBD, but disease duration was longer in LBD. The Parkinson disease stage was similar, but the density of LBs in most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In contrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP and LBD. Double immunostaining demonstrated alpha-synuclein and tau in different neurons with few exceptions. The findings suggest that LBs in PSP are similar in distribution to those in LBD and independent of tau pathology. The greater density of LBs in LBD compared with PSP/LBD may be the result of longer disease duration in LBD, whereas greater neuronal loss in the substantia nigra in PSP/LBD may be the result of vulnerability of this brain region to both disease processes.

Neurodegenerative diseases are often classified based on the abnormal accumulation of synuclein or tau. Traditionally, these disorders have been viewed as distinct clinical and pathological entities. However, advances in molecular genetics and protein biochemistry have shown intriguing overlaps. The most common synucleinopathy, Parkinson's disease, is characterized by extrapyramidal motor dysfunction, whereas the most common tauopathy, Alzheimer's disease, is defined by dementia. Yet there is overlap of clinical features; Parkinson's disease patients frequently have dementia, and Alzheimer's disease patients often manifest parkinsonism. Dementia with Lewy bodies exemplifies the existence of a continuum among these diseases. This overlap extends to the neuropathological findings; the pathognomonic hallmark for one set of disorders, Lewy bodies or neurofibrillary tangles, is present more often than expected in the other set. Moreover, mutations in LRRK2 known to cause parkinsonism are associated not only with dopaminergic neuronal degeneration, but also with the accumulation of synuclein, tau, neither, or both proteins. Other shared genetic features between tauopathies and synucleinopathies also exist. Finally, the known protein interactions between tau and synuclein further highlight the interface. Evidence for the intersection of tauopathies and synucleinopathies indicates the need for an updated disease classification scheme and may have important implications for therapeutic development.