Gene/Protein Disease Symptom Drug Enzyme Compound
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Parkinson's disease is a common age-related neurodegenerative disease characterized pathologically by a loss of dopaminergic neurons in the substantia nigra with resultant depletion of striatal dopamine and presence of Lewy bodies in the remaining neurons. The Lewy body contains numerous functional and structural proteins, including alpha-synuclein and ubiquitin; aggregation of alpha-synuclein is thought to be important in Lewy body formation as well as neurodegeneration, although the detailed mechanisms remain to be defined. Increasing evidence has suggested that mitochondrial dysfunction, increased oxidative stress, and dysfunction of the ubiquitin-proteasome system may be involved in alpha-synuclein aggregation, Lewy body formation, and neurodegeneration. However, how these processes are related to each other is not fully understood, given that there are Parkinsonian animal models as well as human diseases with significant nigral neurodegeneration regardless of whether Lewy bodies form or not. This review summarizes the current related research fields and proposes a proteomic approach to investigate the mechanisms that may dictate alpha-synuclein aggregation, Lewy body formation, and neurodegeneration.
Mol Neurobiol 2004 Jun
PMID:Proteomic approach to studying Parkinson's disease. 1518 Dec 39

Self-assembly of alpha-synuclein resulting in protein aggregates of diverse morphology has been implicated in the pathogenesis of Parkinson's disease and other neurodegenerative disorders known as synucleinopathies. Apart from its biomedical relevance, this aggregation process is representative of the interconversion of an unfolded protein into nanostructures with typical amyloid features. We have used in situ tapping mode atomic force microscopy to continuously monitor the self-assembly of wild-type alpha-synuclein, its disease-related mutants A30P and A53T, and the C-terminally truncated variant alpha-synuclein(1-108). Different aggregation modes were observed depending on experimental conditions, i.e. pH, protein concentration, polyamine concentration, temperature and the supporting substrate. At pH 7.5, in the absence of the biogenic polyamines spermidine or spermine, elongated sheets 1.1(+/-0.2)nm in height and presumably representing individual beta-sheet structures, were formed on mica substrates within a few minutes. Their orientation was directed by the crystalline substructure of the substrate. In contrast, sheet formation was not observed with hydrophobic highly oriented pyrolytic graphite substrates, suggesting that negatively charged surfaces promote alpha-synuclein self-assembly. In the presence of spermidine or spermine 5.9(+/-1.0)nm high spheroidal structures were preferentially formed, sharing characteristics with similar structures previously reported for several amyloidogenic proteins and linked to neurotoxicity. alpha-Synuclein spheroid formation depended critically on polyamine binding to the C terminus, revealing a promoting effect of the C terminus on alpha-synuclein assembly in the bound state. In rare cases, fibril growth from spheroids or preformed aggregates was observed. At pH 5.0, fibrils were formed initially and incorporated into amorphous aggregates in the course of the aggregation process, providing evidence for the potential of amyloid fibril surfaces to act as nucleation sites in amorphous aggregation. This study provides a direct insight into different modes of alpha-synuclein self-assembly and identifies key factors modulating the aggregation process.
J Mol Biol 2004 Jun 25
PMID:Rapid self-assembly of alpha-synuclein observed by in situ atomic force microscopy. 1518 27

Parkinson's disease (PD) is thought to be caused by environmental and genetic factors. Mutations in four genes, alpha-synuclein, parkin, DJ-1, and UCH-L1, have been identified in autosomal inherited forms of PD. The pathogenetic cause for the loss of neuronal cells in PD patients, however, remains to be determined. Due to the rarity of mutations in humans with PD, the analysis of animal models might help to further gain insights into the pathogenesis of familial PD. For UCH-L1, deficiency has been described in gad mice leading to axonal degeneration and formation of spheroid bodies in nerve terminals. Here, we investigated the gene expression pattern of the brain of 3-month-old Uch-l1-deficient gracile axonal dystrophy (gad) mice by microarray analysis. A total of 146 genes were differentially regulated by at least a 1.4-fold change with 103 being up-regulated and 43 being down-regulated compared with age and sex matched wildtype littermate mice. The gene products with altered expression are involved in protein degradation, cell cycle, vesicle transport, cellular structure, signal transduction, and transcription regulation. Most of the genes were modestly regulated, which is in agreement that severe alteration of these pathways might be lethal. Among the genes most significantly down-regulated is the brain-derived neurotrophic factor which might be one aspect of the pathogenesis in gad mice. Interestingly, several subunits of the transcription factor CCAAT/enhancer binding protein are up-regulated, which plays a central role in most altered pathways.
Brain Res Mol Brain Res 2004 Jul 05
PMID:Microarray expression analysis of gad mice implicates involvement of Parkinson's disease associated UCH-L1 in multiple metabolic pathways. 1520 21

alpha-Synuclein is a pre-synaptic protein, the function of which is not completely understood, but its pathological form is involved in neurodegenerative diseases. In vitro, alpha-synuclein spontaneously forms amyloid fibrils. Here, we report that alphaB-crystallin, a molecular chaperone found in Lewy bodies that are characteristic of Parkinson's disease (PD), is a potent in vitro inhibitor of alpha-synuclein fibrillization, both of wild-type and the two mutant forms (A30P and A53T) that cause familial, early onset PD. In doing so, large irregular aggregates of alpha-synuclein and alphaB-crystallin are formed implying that alphaB-crystallin redirects alpha-synuclein from a fibril-formation pathway towards an amorphous aggregation pathway, thus reducing the amount of physiologically stable amyloid deposits in favor of easily degradable amorphous aggregates. alpha-Synuclein acts as a molecular chaperone to prevent the stress-induced, amorphous aggregation of target proteins. Compared to wild-type alpha-synuclein, both mutant forms have decreased chaperone activity in vitro against the aggregation of reduced insulin at 37 degrees C and the thermally induced aggregation of betaL-crystallin at 60 degrees C. Wild-type alpha-synuclein abrogates the chaperone activity of alphaB-crystallin to prevent the precipitation of reduced insulin. Interaction between these two chaperones and formation of a complex are also indicated by NMR spectroscopy, size-exclusion chromatography and mass spectrometry. In summary, alpha-synuclein and alphaB-crystallin interact readily with each other and affect each other's properties, in particular alpha-synuclein fibril formation and alphaB-crystallin chaperone action.
J Mol Biol 2004 Jul 23
PMID:Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity. 1523 75

The field of Parkinson's disease pathogenesis is rapidly evolving from the one of a monolithic and obscure entity into the one of a complex scenario with several known molecular players. The ongoing systematic exploration of the genome holds great promise for the identification of the genetic factors conferring susceptibility to the common non-Mendelian forms of this disease. However, most of the progress of the last 5 years has come from the successful mapping and cloning of genes responsible for rare Mendelian variants of Parkinson's disease. These discoveries are providing tremendous help in understanding the molecular mechanisms of this devastating disease. Here we review the genetics of the monogenic forms of Parkinson's disease. Moreover, we focus on the mechanisms of disease caused by alpha-synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease.
Cell Mol Life Sci 2004 Jul
PMID:Unraveling the pathogenesis of Parkinson's disease--the contribution of monogenic forms. 1524 50

Alpha-synuclein is an abundant neuronal protein that has been linked both to normal synaptic function and to neurodegeneration. Most significantly, mutations in the gene encoding for alpha-synuclein are responsible for Parkinson's disease (PD) in rare familial cases, and the aggregated protein is a major component of Lewy bodies found in sporadic PD. Here we review recent data regarding the structure, the regulation at the transcriptional and posttranslational level, and the physiologic and aberrant functions of alpha-synuclein. We focus in particular on the fibrilization potential of alpha-synuclein and on its link with defects in protein degradation.
Mol Neurobiol 2004 Aug
PMID:Neurobiology of alpha-synuclein. 1524 85

The 140-amino-acid protein alpha-synuclein (alpha-syn) is the major constituent of Lewy bodies. The protein interacts with several intracellular signal transduction pathways. Reasons for onset of abnormal aggregation of alpha-syn are unclear. Metal ions, oxidative stress, and beta-amyloid 1-42 (Abeta1-42) are important induction factors for alpha-syn aggregation. beta-Synuclein (beta-syn) can counteract alpha-syn aggregation. Cross-breeding of beta-syn transgenic mice with animals overexpressing alpha-syn significantly decreased alpha-syn-positive neuronal inclusion bodies and improved motor function. This was an important proof of concept for the role of beta-syn in regulating alpha-syn aggregation. A drug discovery program based on peptide derivatives (N-terminal amino acids 1-15) of beta-syn was initiated. For screening, tissue culture models simulating disease-specific conditions were utilized. They protected against growth factor withdrawal, Abeta toxicity, and oxidative stress. Three peptides were selected (KEGV, SMAKEGV, MDFMKGLSMAKE) for in vivo studies because they also decreased expression of Abeta1-40 and Abeta1-42. First, in vivo experiments were made in human amyloid precursor protein (APP [Swedish and London mutation]) transgenic mice, as well as alpha-syn transgenic mice. Treatment was performed with the peptides as an intraperitoneal injection or as intranasal droplets for 2 mo. Behavioral studies in APP transgenic mice were performed after 1 and 2 mo of treatment and showed clear effects of these peptides.
J Mol Neurosci 2004
PMID:Beta-Synuclein-derived peptides with neuroprotective activity: an alternative treatment of neurodegenerative disorders? 1531 65

Macromolecular crowding is expected to have several significant effects on protein aggregation; the major effects will be those due to excluded volume and increased viscosity. In this report we summarize data demonstrating that macromolecular crowding may lead to a dramatic acceleration in the rate of protein aggregation and formation of amyloid fibrils, using the protein alpha-synuclein. The aggregation of alpha-synuclein has been implicated as a critical factor in development of Parkinson's disease. Various types of polymers, from neutral polyethylene glycols and polysaccharides (Ficolls, dextrans) to inert proteins, are shown to accelerate alpha-synuclein fibrillation. The stimulation of fibrillation increases with increasing length of polymer, as well as increasing polymer concentration. At lower polymer concentrations (typically up to approximately 100 mg/ml) the major effect is ascribed to excluded volume, whereas at higher polymer concentrations evidence of opposing viscosity effects become apparent. Pesticides and metals, which are linked to increased risk of Parkinson's disease by epidemiological studies, are shown to accelerate alpha-synuclein fibrillation under conditions of molecular crowding.
J Mol Recognit
PMID:The effect of macromolecular crowding on protein aggregation and amyloid fibril formation. 1536 5

Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype-phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed alpha-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.
Mol Genet Metab
PMID:Gaucher disease: complexity in a "simple" disorder. 1546 15

Using proteomics, we investigated the temporal expression profiles of proteins in rat sciatic nerve after experimental crush. Extracts of sciatic nerves collected at 5, 10, and 35 days after injury were analyzed by two-dimensional gel electrophoresis and quantitative image analysis. Of the approximately 1,500 protein spots resolved on each gel, 121 showed significant regulation during at least one time point. Using cluster analysis, these proteins were grouped into two expression profiles of down-regulation and four of up-regulation. These profiles mainly reflected differences in cellular origins in addition to different functional roles. Mass spectrometric analysis identified 82 proteins pertaining to several functional classes, i.e. acute-phase proteins, antioxidant proteins, and proteins involved in protein synthesis/maturation/degradation, cytoskeletal (re)organization, and in lipid metabolism. Several proteins not previously implicated in nerve regeneration were identified, e.g. translationally controlled tumor protein, annexin A9/31, vitamin D-binding protein, alpha-crystallin B, alpha-synuclein, dimethylargininases, and reticulocalbin. Real-time PCR analysis of selected genes showed which were expressed in the nerve versus the dorsal root ganglion neurons. In conclusion, this study highlights the complexity and temporal aspect of the molecular process underlying nerve regeneration and points to the importance of glial and inflammatory determinants.
Mol Cell Proteomics 2005 Feb
PMID:Proteomics of the injured rat sciatic nerve reveals protein expression dynamics during regeneration. 1550 15


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