Search

Movement disorders as well as peripheral neuropathies are extremely frequent in the general population; therefore, it is not uncommon to encounter patients with both these conditions. Often, the coexistence is coincidental, due to the high incidence of common causes of peripheral neuropathy, such as diabetes and other age-related disorders, as well as of Parkinson disease (PD), which has a typical late onset. Nonetheless, there is broad evidence that PD patients may commonly develop a sensory and/or autonomic polyneuropathy, triggered by intrinsic and/or extrinsic mechanisms. Similarly, some peripheral neuropathies may develop some movement disorders in the long run, such as tremor, and rarely dystonia and myoclonus, suggesting that central mechanisms may ensue in the pathogenesis of these diseases. Although rare, several acquired or hereditary causes may be responsible for the combination of movement and peripheral nerve disorders as a unique entity, some of which are potentially treatable, including paraneoplastic, autoimmune and nutritional aetiologies. Finally, genetic causes should be pursued in case of positive family history, young onset or multisystemic involvement, and examined for neuroacanthocytosis, spinocerebellar ataxias, mitochondrial disorders and less common causes of adult-onset cerebellar ataxias and spastic paraparesis. Deep phenotyping in terms of neurological and general examination, as well as laboratory tests, neuroimaging, neurophysiology, and next-generation genetic analysis, may guide the clinician toward the correct diagnosis and management. [ABSTRACT FROM AUTHOR]

The primary objective of this research is to further examine the events occurring during the active or burst phase by focusing on the aggregation of the Syn amyloid protein. Regarding this aspect, it was initially conducted rapid temperature variations using stopped-flow spectrometry and tyrosyl group fluorescence emission detection, within the initial 500 milliseconds in buffered Syn solutions at pH 7, exploring various temperature ranges to investigate protein aggregation. The results obtained were contrasted with results obtained for the Nα-acetyl-L-tyrosinamide (NAYA) parent compound in the same conditions. The utilization of the NAYA compound is suitable as it mimics the peptide bonds in proteins and contains a tyrosyl group resembling the four tyrosyl groups found in the Syn protein structure (the protein has no tryptophan residues). Furthermore, the NAYA compound adopts an intramolecularly hydrogen-bonded structure even in an aqueous solution, similar to the interactions seen in the hydrophilic face of β-sheets. Additionally, the Syn protein system can exhibit the presence of β-sheets as a result of the existence of very low abundant Syn amyloid precursor forms or nuclei during the initial stages of the protein aggregation. Thus, a relationship is present between the molecular processes in the NAYA and Syn protein systems, making the NAYA’s application crucial in this research. Moreover, to aid in understanding the results, it was also compared the events during the quiescent or inactive phase (30–500 milliseconds) with those in the burst phase (up to 10 milliseconds) using stopped-flow spectrometry conditions. Steady-state measurements were beneficial in comprehending the occurrences in both the quiescent and burst phases examined. Although protein aggregation and disaggregation were observed during the quiescent phase, determining these processes in the burst phase was more challenging. In the latter case, the aggregation of the Syn protein is actually initiated by the interaction of the intrinsically disordered Syn monomers. In the quiescent phase, first-order rate constants were measured and analysis showed that Syn protein aggregation and disaggregation occur simultaneously. At lower temperatures, early protein disaggregation outweighs protein aggregation whereas at higher temperatures protein disaggregation and aggregation are rather similar. It is also need to highlight that the burst phase, while distinct from the quiescent phase, can be considered as a possible structural phase for obtaining details about the aggregation of this specific disordered protein in solution on a very short timescale. [ABSTRACT FROM AUTHOR]

Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded α-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that α-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up α-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. [ABSTRACT FROM AUTHOR]

The effects of bacterial LPS on the expression of early apoptosis marker (annexin V) and immunoreactive α-synuclein in mononuclear leukocytes of the mesenteric lymph nodes of rats were studied in vivo and in vitro. Injection of LPS increased the number of lymphocytes with high expression of immunoreactive α-synuclein in cell nucleus and cytoplasm (by 68.6±8.1%) and stimulated apoptosis in this population (by 96.0±3.6% of the control). The expression of α-synuclein in macrophages increased only in the cytoplasm and this increase was not paralleled by stimulation of apoptosis in these cells. The data indicate that LPS-induced elevation of α-synuclein in lymphocytes is a component of the mechanism of programmed death in these cells. The increase of α-synuclein expression in macrophages can be related to processes associated with their stimulation. [ABSTRACT FROM AUTHOR]

A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (ADNLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest. [ABSTRACT FROM AUTHOR]

Many groups have generated α-synuclein (α-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as α-syn deposits, compromised function of dopaminergic neurons, fibrillization of α-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of α-syn tg mice may be required. We predict that β-synuclein (β-syn), the homologue of α-syn, might be a key molecule for this purpose. Although β-syn is a neuroprotective molecule counteracting the α-syn pathology in tg mice, it was previously shown that both β-syn and γ-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson’s disease and DLB. Furthermore, two missense mutations (P123H and V70M) of β-syn were recently identified in DLB. These mutants of β-syn were prone to aggregate in vitro and overexpression of these mutant β-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of β-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant β-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional α-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant β-syn/α-syn might be characterized by a more accelerated phenotype of synucleinopathies. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells, synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD. [ABSTRACT FROM AUTHOR]

Increased α-synuclein expression may be involved in the pathogenesis of Parkinson’s disease (PD). We investigated the association of Rep1 microsatellite and RsaI T-to-C substitution in the α-synuclein promoter region with the risk of PD by a case-control study. The RsaI C/C genotype and C allele were found less frequently in PD patients than in controls. A reduced risk of the Rep1- RsaI 0-C haplotype (OR = 0.57, 95% CI = 0.36–0.90) with PD was evident. The quantitative real-time PCR study showed that the α-synuclein mRNA expression was increased (although not significantly) in PD patients with RsaI T/T genotype or Rep1- RsaI 0-T haplotype as compared to T/C genotype or 0-C haplotype. Reporter constructs containing the RsaI C allele drove significantly lower transcriptional activity compared with the RsaI T allele in both IMR32 and 293 cells. The findings suggest that the RsaI T-to-C substitution may have a functional relevance to the susceptibility to PD. [ABSTRACT FROM AUTHOR]

The etiologic basis of Parkinson’s disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural chemicals, may contribute to the pathogenesis of this disorder. Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Recently, agricultural chemicals, when administrated systemically, have been shown to reproduce specific features of PD in rodents, thus opening new routes for the development of animal models for this disorder. In addition to a brief historical overview of the toxin-induced PD models, this study provides a detailed description of exiting models in which Parkinsonism is initiated via the exposure of animals to such agricultural chemicals as rotenone, paraquat, and maneb. Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed. [ABSTRACT FROM AUTHOR]

Parkinsonism is a clinical syndrome characterized by akinesia, muscular rigidity, and resting tremor. The most frequent cause of parkinsonism is Parkinson’s disease (PD). Progressive loss of substantia nigra neurons together with the occurrence of Lewy bodies are considered essential neuropathological features of PD. Recent neuropathological studies suggest that nigral degeneration is only part of a more extended brain degeneration that starts in the medulla oblongata and then spreads to the mesencephalon and cerebral cortex. Correspondingly, the clinical symptoms occurring in PD go far beyond parkinsonism. Depending on the disease stage, autonomic dysfunction, olfactory disturbances, depression, and dementia are frequently encountered in PD. These neuropathological and clinical observations have major implications for future research in PD. In particular, the analysis of the properties that the neuronal cell types involved in PD have in common and that might make them susceptible to degeneration is essential. [ABSTRACT FROM AUTHOR]

Following the identification of mutations in α-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile, several neurodegenerative diseases have been shown to accumulate a-synuclein in neuronal and glial cells summarizing this group of diseases as synucleinopathies. All currently known gene defects causing PD alter the ubiquitin-proteasomal pathway of protein degradation. Identification of these disease mutations allows studying the functional consequences which lead to cellular dysfunction and cell death in cell culture and transgenic animal models, to identify therapeutic targets and to test potential protective strategies in these models. [ABSTRACT FROM AUTHOR]

dministration of autologous macrophages isolated from the abdominal cavity and stimulated in vitro with bacterial LPS to rats increased blood level of antibodies against α-synuclein. Antibody titer reached its maximum during week 5 of the experiment and exceeded the levels of anti-α-synuclein antibodies appeared in response to transplantation of non-stimulated macrophages. Brain immunohistochemistry showed that additional administration of LPS (250 μg/kg) to animals during week 4 after injection of LPS-stimulated macrophages led to α-synuclein accumulation in 9.4±3.2% dopaminergic neurons of the substantia nigra. These findings attest to induction of humoral immune response to α-synuclein in rats after administration of autologous LPS-stimulated macrophages, which can affect α-synuclein metabolism in dopaminergic neurons of the brain. [ABSTRACT FROM AUTHOR]