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PubMed2005

Alpha-synuclein-positive structures induced in leupeptin-infused rats.

Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.

Animals↗

PubMed2006

Osteopontin expression in substantia nigra in MPTP-treated primates and in Parkinson's disease.

Parkinson's disease (PD) is characterised by the loss of dopaminergic neurones in the substantia nigra (SN) but the pathogenic mechanism remains unknown. Cell death involves oxidative stress and inflammatory mechanisms, and these may be altered by the actions of the glycosylated phosphoprotein osteopontin (OPN). OPN is present in the rat SN, but its presence in human and non-human primate brain has not been extensively studied. Both OPN mRNA and protein were present in the normal marmoset SN, and OPN protein was localised to nigral neurones although these were not dopaminergic cells and it was not present in glial cells. In contrast, OPN protein was found in dopaminergic neurones in the normal human SN but again not in glial cells with some accumulation in the extracellular matrix. Following MPTP treatment of common marmosets, OPN protein expression was decreased, although its mRNA levels were unchanged and it was not present in either activated microglia or astrocytes. In the SN in PD, OPN protein expression was decreased in the remaining dopaminergic neurones and it was present in activated microglia but not in astrocytes. This was not specific to PD as OPN protein expression was also decreased in the SN in multiple system atrophy and progressive supranuclear palsy with an identical localisation of the protein. The presence of OPN in the normal human and non-human primate SN coupled to its decreased expression following nigral cell degeneration suggests that it may play an important role in dopaminergic neurone survival.

Aged↗

PubMed2006

Parkinsonian syndromes.

The term parkinsonian syndromes refers to a group of disorders whose clinical features overlap those of idiopathic Parkinson's disease. The four major entities include three important neurodegenerations, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, and a lacunar cerebrovascular disorder, vascular parkinsonism. This article reviews the epidemiology, pathology, clinical features, diagnosis, and management of these disorders.

Cerebrovascular Disorders↗

PubMed2004

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS: We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinson's disease and 17 healthy subjects. RESULTS: PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS: Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.

Adult↗

PubMed2006

Increased lifespan in transgenic Caenorhabditis elegans overexpressing human alpha-synuclein.

alpha-Synuclein is a short 14-kDa protein found in pathological lesions of age-related neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple system atrophy. Its overexpression in transgenic mice, rats, Drosophila melanogaster, and Caenorhabditis elegans recapitulates many of the pathologic features observed in human Parkinson's disease including loss of dopaminergic neurons and motor deficits. Integrated transgenic C. elegans lines were generated that overexpress either human wildtype (WT) or mutant (A53T) forms. These transgenic lines demonstrated approximately 25% increase in lifespan (p<0.0001) compared to controls. When the transgenes were crossed into long-lived daf-2 (m577) or daf-2 (e1370) genetic backgrounds, the lifespan increase was also approximately 25% in comparison to the corresponding daf-2 strains (p<0.05). Pharyngeal pumping and egg laying were significantly decreased in the overexpressing transgenic lines, and lifespan increases were attenuated when lines were grown on thick bacterial lawns, suggesting that caloric restriction may explain some of the effects on lifespan. These studies provide initial evidence for a beneficial role of human alpha-synuclein in influencing lifespan.

Aging↗

PubMed2006

Dynamic imbalance in gait ataxia. Characteristics of plantar pressure measurements.

The present study was designed to evaluate the interaction between disequilibrium and irregular stepping components of ataxic gait. For this purpose, we compared the walking patterns of patients with cerebellar dominant multiple system atrophy (MSAc, n = 8), spinocerebellar ataxia type 6 (SCA6, n = 4) and 16q-linked autosomal dominant cortical cerebellar atrophy (16q-linked ADCA, n = 6), and 6 normal subjects, by measuring toe and heel plantar pressures. In healthy subjects, the heel contacted the floor at step-in followed by an immediate shift of the center of pressure (COP) to the contacted leg. In ataxic gait, however, both the heel and toes simultaneously contacted the floor and the disappearance of the immediate shift of the COP was noted. These changes appeared to be nonspecific compensations for the instability. Examination of two parameters of ataxia-specific changes showed that prolongation of the double support period was associated with proportionate increase in the coefficients of variance of the plantar pressures and the step lengths on walking of patients with SCA6, but not those with MSAc and 16q-linked ADCA. Our results suggest that disequilibrium and irregularity are two separate and independent components of cerebellar ataxic gait.

Adult↗

PubMed2004

Sleep and quantitative EEG in neurodegenerative disorders.

This paper reviews current knowledge on sleep problems, sleep architecture changes and quantitative EEG alteration brought on by various neurodegenerative diseases, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), REM sleep behavior disorder (RBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy MSA, Huntington's disease and Creutzfeldt-Jakob disease, in comparison to normal aging. The study of sleep variables and that of the spectral composition of the EEG can provide valuable information for understanding the pathophysiology and for assisting the diagnosis of neurodegenerative diseases.

Aged↗

PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗

PubMed2006

Delusional parasitosis and the dopamine transporter. A new insight of etiology?

Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP and decreased striatal DAT-functioning, trying to give a new insight into the pathophysiologically mechanism involved. The hypothesis provides supporting evidence that increased levels of extracellular dopamine in the striatum of DP-patients is likely to be the result of decreased DAT-functioning and not increased rates of release. The hypothesis can be investigated simply by dopamine transporter imaging in patients with DP.

Cocaine↗

PubMed2005

Pathogenic effects of alpha-synuclein aggregation.

Biochemical and genetic evidence point towards alpha-synuclein aggregation as having a pivotal role in the onset and progression of several neurodegenerative disorders, including Parkinson's disease, multiple system atrophy and Lewy body dementia. We review recent data on how alpha-synuclein aggregates may impact on cellular homeostatic mechanisms including cellular transport and degradation and transcriptional regulation. alpha-Synuclein aggregates can exist as several molecular species and their different features are discussed in the context of the methodologies used for their study and the many chemical and physical factors that influence their formation.

Animals↗

PubMed2026

Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.

Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.

Humans↗

PubMed2004

Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies.

The novel basic, heat-stable tubulin polymerization promoting protein TPPP/p25 is associated with microtubules in vitro and can induce the formation of aberrant microtubule assemblies. We show by 1H-NMR spectroscopy that TPPP/p25 is natively unfolded. Antisera against peptide 186GKGKAGRVDLVDESG200NH2 (186-200) are highly specific to TPPP/p25. Immunohistochemistry and confocal microscopy demonstrates that TPPP/p25 is enriched in filamentous alpha-synuclein bearing Lewy bodies of Parkinson's (PD) and diffuse Lewy body disease (DLBD), as well as glial inclusions of multiple system atrophy (MSA). There is a correlation between TPPP/p25 and alpha-synuclein immunoreactivity in Western blot. In contrast, TPPP/p25 is not associated with abnormally phosphorylated tau in various inclusions of Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). However, electron microscopy confirms clusters of TPPP/p25 immunoreactivity along filaments of unstructured but not compact neurofibrillary tangles in Alzheimer's disease (AD). TPPP/p25 seems to be a novel marker of alpha-synucleinopathies.

Aged↗

PubMed2006

Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein.

Alpha-synuclein containing cellular inclusions are a hallmark of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. A genome wide expression screen was performed in C. elegans overexpressing both wild-type and A53T human alpha-synuclein. 433 genes were up- and 67 genes down-regulated by statistical and fold change (> or <2) criteria. Gene ontology (GO) categories within the regulated gene lists indicated over-representation of development and reproduction, mitochondria, catalytic activity, and histone groups. Seven genes (pdr-1, ubc-7, pas-5, pas-7, pbs-4, RPT2, PSMD9) with function in the ubiquitin-proteasome system and 35 mitochondrial function genes were up-regulated. Nine genes that form histones H1, H2B, and H4 were down-regulated. These results demonstrate the effects of alpha-synuclein on proteasome and mitochondrial complex gene expression and provide further support for the role of these complexes in mediating neurotoxicity. The results also indicate an effect on nuclear protein genes that suggests a potential new avenue for investigation.

Animals↗

PubMed2006

Vitamin A potently destabilizes preformed alpha-synuclein fibrils in vitro: implications for Lewy body diseases.

Alpha-synuclein (alphaS) is the major component of the filamentous inclusions that constitute defining characteristics of Lewy body diseases (LBD) and multiple system atrophy (MSA). Clinically, antioxidant vitamins, such as vitamin E and the vitamin-like substance coenzyme Q10, have been used in the treatment of LBD with some efficacy. Using fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy, here we examined the effects of ten antioxidant vitamins and vitamin-like substances, vitamin A (retinol, retinal and retinoic acid), beta-carotene, vitamins B2, B6, C, E, coenzyme Q10 and alpha-lipoic acid, on the formation of alphaS fibrils (falphaS) and on preformed falphaS. Among them, vitamin A, beta-carotene and coenzyme Q10 dose-dependently inhibited the formation of falphaS. Moreover, they also dose-dependently destabilized preformed falphaS. With such potent anti-fibrillogenic as well as fibril-destabilizing activities, these compounds could be useful in the treatment and prevention of LBD and MSA.

Antioxidants↗

PubMed2003

Expression of nestin in Purkinje cells in patients with Creutzfeldt-Jakob disease.

Nestin is one of the intermediate filament proteins and mainly expressed during the development of the central nervous system. We examined the cerebellum of patients with Creutzfeldt-Jakob disease (CJD), multiple system atrophy and amyotrophic lateral sclerosis, using anti-human nestin antibodies. The antibodies strongly immunostained the cytoplasm, dendrites and torpedoes of Purkinje cells in CJD. However, Purkinje cells in other neurodegenerative disorders were not nestin-immunoreactive. Nestin immunoreactivities became more marked as the pathological severity in the cerebellum increased. Our findings suggest that nestin is strongly expressed in Purkinje cells in pathologically advanced CJD and show the possibility that Purkinje cells are being reactivated to promote survival.

Aged↗

PubMed2005

The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases.

Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features. We screened for the most common LRRK 2 mutation in a series of patients with Parkinson's Disease, Alzheimer's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease.

Aged↗

PubMed2005

Association between supine cerebral perfusion and symptomatic orthostatic hypotension.

The goal of this study was to investigate whether the supine resting perfusion of brain tissue in symptomatic patients suffering from orthostatic hypotension (OH) is changed compared to control subjects and whether an association exists between the resting perfusion and the severity of OH. Ten symptomatic OH patients and 8 control subjects were included in this study. One patient was retrospectively excluded because he suffered from multiple system atrophy. Systolic and diastolic blood pressure changes were measured during a tilting bed procedure. Cerebral blood flow, cerebral blood volume and mean transit time were determined by bolus-tracking perfusion MRI and correlated with blood pressure changes. Cerebral blood volume was significantly increased in OH patients compared with control subjects for white matter (P = 0.019) and the mean transit time was significantly increased for gray (P = 0.010) and white matter (P = 0.015). The cerebral blood flow of the gray (r = 0.74, P = 0.022) and white matter (r = 0.75, P = 0.020) was significantly, positively correlated with systolic blood pressure changes. The mean transit time in white matter was significantly, negatively correlated with systolic blood pressure changes (r = -0.68, P = 0.045). This study suggests that in symptomatic patients with OH the cerebral perfusion of the brain in the resting, supine position correlates with the severity of OH as measured by postural changes in blood pressure.

Aged↗

PubMed2004

Caribbean parkinsonism and other atypical parkinsonian disorders.

Atypical parkinsonism (AP) is a term applied to disorders characterized by parkinsonism that evolves rapidly, with poor or transient response to levodopa, or has other associated features such as early falls and postural instability, early autonomic failure, supranuclear gaze palsy, pyramidal or cerebellar signs, alien hand syndrome or severe ideomotor apraxia. The most common AP are multiple system atrophy, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Other APs include Caribbean parkinsonism (CP) and parkinsonism-dementia complex of Guam (PDC). In this review we provide an update in etiology, neuropathology, diagnosis and treatment of atypical parkinsonian disorders associated with protein tau deposit, also known as tauopathies.

Animals↗