Search PubMed⌕ Search

Biomedical subjects

Daniela Berg

Publications and source records attributed to Daniela Berg.

At least 19 recordsLinked to original sources
PubMed2006

Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra.

Iron mediated oxidative stress is known to contribute to the neurodegenerative process in Parkinson's disease (PD). Although there are hints that genes involved in brain iron metabolism might be involved in the pathogenesis of PD in some instances, it is still not known whether the increase in brain iron content constitutes a primary or secondary event in the disease cascade. Recent studies on the role of hemochromatosis gene (HFE) mutations in PD vary from a protective effect of C282Y heterozygosity, no effect of the C282Y or H63D mutation to an increased risk for PD in C282Y mutation carriers. In this study, analyzing the whole coding region of the HFE gene by dHPLC in 278 PD patients, priorly characterized by transcranial sonography for increased iron content of the substantia nigra (SN), we did not find an association of the common HFE mutations and PD. However, we identified two novel variants (K92N and I217T) each in a single PD patient. These variations were not found in any of the controls. Future studies are necessary to reveal a possible functional relevance of these mutations for PD. Our results indicate that mutations in the HFE gene are not a common cause for PD with increased iron levels of the SN.

Aged↗
PubMed2006

Substantia nigra hyperechogenicity as a marker of predisposition and slower progression in Parkinson's disease.

Increased echogenic size (hyperechogenicity) of the substantia nigra (SN) is a characteristic transcranial sonography finding in patients with Parkinson's disease (PD). The SN echogenic size does not change in the course of the disease. In order to see whether this stable ultrasound marker may give any implications for the rate of PD progression, we sonographically investigated 16 PD patients in whom the rate of progression had been determined by serial 18-fluorodopa positron emission tomography over a follow-up period of 65.7+/-26.7 months. We found a significant negative correlation between the right-to-left averaged SN echogenic size and the rate of disease progression in the caudate nucleus and in the putamen. There was a tendency towards a younger age at symptom onset in patients with SN hyperechogenicity. It may therefore be hypothesized that a differing influence of factors determining SN echogenicity early in life and impairing forces occurring later in life may account for different pathogenetic subgroups of idiopathic PD.

Adult↗
PubMed2006

Iron metabolism in Parkinsonian syndromes.

Growing evidence suggests an involvement of iron in the pathophysiology of neurodegenerative diseases. Several of the diseases are associated with parkinsonian syndromes, induced by degeneration of basal ganglia regions that contain the highest amount of iron within the brain. The group of neurodegenerative disorders associated with parkinsonian syndromes with increased brain iron content can be devided into two groups: (1) parkinsonian syndromes associated with brain iron accumulation, including Parkinson's disease, diffuse Lewy body disease, parkinsonian type of multiple system atrophy, progressive supranuclear palsy, corticobasal ganglionic degeneration, and Westphal variant of Huntington's disease; and (2) monogenetically caused disturbances of brain iron metabolism associated with parkinsonian syndromes, including aceruloplasminemia, hereditary ferritinopathies affecting the basal ganglia, and panthotenate kinase associated neurodegeneration type 2. Although it is still a matter of debate whether iron accumulation is a primary cause or secondary event in the first group, there is no doubt that iron-induced oxidative stress contributes to neurodegeneration. Parallels concerning pathophysiological as well as clinical aspects can be drawn between disorders of both groups. Results from animal models and reduction of iron overload combined with at least partial relief of symptoms by application of iron chelators in patients of the second group give hope that targeting the iron overload might be one possibility to slow down the neurodegenerative cascade also in the first group of inevitably progressive neurodegenerative disorders.

Animals↗
PubMed2006

Predictive value of transcranial sonography in the diagnosis of Parkinson's disease.

Transcanial sonography (TCS) is increasingly applied in the diagnosis of Parkinson's disease (PD), but investigator bias may influence the results of examination. Blinding the sonographer to the clinical diagnosis of 42 PD patients and 35 controls, we obtained a positive predictive value of 85.7% and a negative predictive value of 82.9% in the diagnosis of PD solely by interpreting the results of TCS, indicating that TCS is a valuable additional tool in the diagnosis of PD.

Aged↗
PubMed2006

Disturbance of iron metabolism in Parkinson's disease -- ultrasonography as a biomarker.

A central role of iron in the pathogenesis of Parkinson's disease (PD) has been discussed for many years. So far, however, a biomarker indicating increased iron levels in the substantia nigra (SN) in PD patients has been missing. Performing transcranial ultrasound we detected an increased area of SN echogenicity as a typical echofeature in PD, visible already in the early stages of the disease and in subjects with subclinical impairment of the nigrostriatal system. Animal studies and post mortem analyses of human brain tissue revealed that this echofeature is associated with increased iron levels of the substantia nigra as well as a reduced neuromelanin content. The apparently autosomal dominant inheritance of this echofeature in relatives of patients with idiopathic PD indicates a primary role of disturbances of iron metabolism in PD. Consequently performed mutation analyses in genes involved in brain iron metabolism lead to the discovery of specific mutations in the ferritin-H, IRP2 and HFE gene in single PD patients. Moreover, variations in the ceruloplasmin gene were found to be associated with PD or SN hyperechogenicity. Functional relevance of some of these mutations for iron metabolism could be proven. Therefore, SN hyperechogenicity can be regarded as biomarker for both: impairment of the nigrostriatal system and increased iron levels of the SN. Future studies aim at substantiating the hypothesis that healthy subjects with SN hyperechogenicity indeed represent a population at risk for nigrostriatal degeneration, which would have a significant impact on therapeutical options.

Animals↗
PubMed2005

Functional relevance of ceruloplasmin mutations in Parkinson's disease.

Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.

Alleles↗
PubMed2005

Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

Amino Acid Sequence↗
PubMed2005

Multiple regions of alpha-synuclein are associated with Parkinson's disease.

alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.

Age Factors↗
PubMed2005

Common variants of LRRK2 are not associated with sporadic Parkinson's disease.

Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.

Age of Onset↗
PubMed2005

Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson's disease.

Using transcranial sonography, an area of hyperechogenicity at the substantia nigra (SN) may be detected as a typical marker in patients with Parkinson's disease (PD) as well as in approximately 9% of healthy subjects vulnerable to nigrostriatal impairment. In this longitudinal study, we provide evidence that the area of SN hyperechogenicity does not change in the course of PD. In conjunction with earlier findings in children and adolescents, this evidence indicates that, from late adolescence onward, this ultrasound finding is a trait marker for nigrostriatal vulnerability.

Adult↗
PubMed2005

Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients.

Data on the frequency of alpha-synuclein mutations in Parkinson's disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the alpha-synuclein gene are rare and suggest that other factors contribute to alpha-synuclein aggregation in the majority of PD patients.

Aged↗
PubMed2005

In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage.

Early diagnosis of Parkinson's disease (PD) in nonsymptomatic patients is a key issue. An increased echogenicity of the substantia nigra (SN) was found previously in Parkinsonian patients and in a low percentage of healthy adults. These nonsymptomatic subjects also showed a reduced 18F-dopa uptake in striatum, suggesting a preclinical injury of the nigrostriatal system that could later proceed into PD. To investigate the ability of ultrasonography to detect markers of SN degeneration, such as iron deposition and neuromelanin depletion, we scanned postmortem brains from normal subjects at different ages by ultrasound and measured the echogenic area of the SN. The SN was then dissected and used for histological examinations and determination of iron, ferritin, and neuromelanin content. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. Multivariate analysis carried out considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. In PD, a typical loss of neuromelanin and increase of iron is observed in this brain area. The finding of a positive correlation between iron and ferritin levels and a negative correlation of neuromelanin content with the area of echogenicity at the SN could therefore provide an interesting basis for diagnosis and therapeutic follow-up studies in PD.

Apoferritins↗
PubMed2004

Redox imbalance.

Substantial evidence implies that redox imbalance attributable to an overproduction of reactive oxygen species or reactive nitrogen species that overwhelm the protective defense mechanism of cells contributes to all forms of Parkinson's disease. Factors such as dopamine, neuromelanin, and transition metals may, under certain circumstances, contribute to the formation of oxygen species such as H(2)O(2), superoxide radicals, and hydroxyl radicals and react with reactive nitrogen species such as nitric oxide or peroxinitrite. Mitochodrial dysfunction and excitotoxicity may be a cause and a result of oxidative stress. Consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage, and interference of reactive oxygen species with signal transduction pathways. These consequences become even more harmful when genetic variations impair the normal degradation of altered proteins. Therefore, therapeutic strategies must aim at reducing free-radical formation and scavenging free-radicals.

Animals↗
PubMed2004

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.

Animals↗
PubMed2004

Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).

Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [(18)F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein.

Adult↗
PubMed2004

Postnatal decrease in substantia nigra echogenicity. Implications for the pathogenesis of Parkinson's disease.

Increased echogenicity of the substantia nigra (SN) on transcranial ultrasonography (TCS) is a typical sign in Parkinson's disease (PD). Detected in healthy adults it is assumed to represent a risk factor for nigral injury. We studied at which time point of brain maturation increased signal intensity may occur by performing TCS scans in 109 newborns and children aged 0-192 months. While newborns regularly exhibit SN hyperechogenicity, this echofeature decreases substantially during the first years of life. As SN echogenicity is related to the tissue iron content in adults our findings suggest a failure in SN iron metabolism in some children with increased echogenicity during development which can be disclosed by TCS.

Adolescent↗
PubMed2004

Evaluation of the ventricular system in children using transcranial ultrasound: reference values for routine diagnostics.

In children, evaluation of the size of the ventricular system is important. Transcranial Doppler sonography (TCD), a broadly available and easily applicable method that is not hampered by side effects, such as radiation, is a valuable tool for routine examinations. However, standard TCD values of the ventricular system are lacking. In this study, we performed TCD through the temporal acoustic bone window in a large cohort of 1693 healthy children. Of these, 157 had to be excluded because of insufficient bone windows. In the remaining children, a mean width of 1.4 +/- 0.8 mm for the third ventricle, 14.4 +/- 0.8 mm for the right and 14.6 +/- 0.7 mm for the left cella media, and 1.6 +/- 0.7 mm for the right and 1.9 +/- 0.8 mm for the left temporal horn were measured. Side differences are indicated and values are given in relation to age and gender. Inter-rater reproducibility obtained in 25 children was adequate, with no significant difference between the two measurements in any of the parts of the ventricular system measured, rendering these values suitable for reference.

Adolescent↗