Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial dysfunction has been associated with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant alpha-synuclein aggregates and a reduction in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP reduction. Microscopic analyses showed a progressive evolution of small aggregates of alpha-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, gamma-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-positive, suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metabolism and was partially inhibited by proteasome inhibitors. These results suggest that the formation of alpha-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism.
 ...
PMID:Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. 1172 69

Neurodegenerative disorders such as Parkinson's disease (PD) and 'dementia with Lewy bodies' (DLB) are characterized pathologically by selective neuronal death and the appearance of intracytoplasmic protein aggregates (Lewy bodies). The process by which these inclusions are formed and their role in the neurodegenerative process remain elusive. In this study, we demonstrate a close relationship between Lewy bodies and aggresomes, which are cytoplasmic inclusions formed at the centrosome as a cytoprotective response to sequester and degrade excess levels of potentially toxic abnormal proteins within cells. We show that the centrosome/aggresome-related proteins gamma-tubulin and pericentrin display an aggresome-like distribution in Lewy bodies in PD and DLB. Lewy bodies also sequester the ubiquitin-activating enzyme (E1), the proteasome activators PA700 and PA28, and HSP70, all of which are recruited to aggresomes for enhanced proteolysis. Using novel antibodies that are specific and highly sensitive to ubiquitin-protein conjugates, we revealed the presence of numerous discrete ubiquitinated protein aggregates in neuronal soma and processes in PD and DLB. These aggregates appear to be being transported from peripheral sites to the centrosome where they are sequestered to form Lewy bodies in neurons. Finally, we have shown that inhibition of proteasomal function or generation of misfolded proteins cause the formation of aggresome/Lewy body-like inclusions and cytotoxicity in dopaminergic neurons in culture. These observations suggest that Lewy body formation may be an aggresome-related event in response to increasing levels of abnormal proteins in neurons. This phenomenon is consistent with growing evidence that altered protein handling underlies the etiopathogenesis of PD and related disorders.
 ...
PMID:Aggresome-related biogenesis of Lewy bodies. 1247 81

Parkin is a protein-ubiquitin E3 ligase linked to Parkinson's disease. Although several substrates of parkin have been identified, the subcellular location for parkin to recognize and ubiquitinate its targets is unclear. Here we report that parkin was accumulated in the centrosome when SH-SY5Y or transfected HEK293 cells were treated with the proteasome inhibitor lactacystin. The specific recruitment of parkin was dependent on concentration and duration of the treatment, and was accompanied by the centrosomal accumulation of ubiquitinated proteins and CDCrel-1, a substrate of parkin. The recruitment of parkin was apparently mediated through its binding to gamma-tubulin, which has been shown to accumulate in the centrosome in response to misfolded proteins. Furthermore, the effect was abrogated by the microtubule-depolymerizing drug colchicine or the microtubule-stabilizing drug taxol, which indicates that the intact microtubule network is required for the centrosomal recruitment of parkin. Taken together, our data suggest that the lactacystin-induced accumulation of parkin in the centrosome plays a significant role in the ubiquitination of misfolded substrates accumulated there. This process may provide a subcellular locale for parkin to ubiquitinate and degrade protein aggregates critically involved in the pathogenesis of Parkinson's disease.
 ...
PMID:Parkin is recruited to the centrosome in response to inhibition of proteasomes. 1292 31

Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with gamma-tubulin, acetylated alpha-tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.
 ...
PMID:Inhibition of proteasomal activity causes inclusion formation in neuronal and non-neuronal cells overexpressing Parkin. 1293 72

Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing alpha-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, gamma-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of alpha-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of nonapoptotic cells but only in 10% of apoptotic cells. Additionally, alpha-synuclein-induced apoptosis was not coupled with increased prevalence of aggresome-bearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of alpha-synuclein and synphilin-1.
 ...
PMID:Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. 1462 98

alpha-Synuclein is a major component of intracytoplasmic inclusions including Lewy bodies (LB), Lewy neurites (LN) and glial cytoplasmic inclusions, and plays a key role in neurodegenerative processes in Parkinson's disease (PD) and other synucleinopathies. Although the molecular mechanisms of the disease process still remain to be elucidated, recent studies have suggested that an interaction between reactive oxygen species (ROS) and alpha-synuclein may be closely associated with the initiation and/or the progression of synucleinopathies. In this study, we established human dopaminergic SH-SY5Y cell lines overexpressing wild-type or mutant alpha-synuclein and exposed them to various ROS generators. After the exposure to ROS, alpha-synuclein aggregates were formed in the cytoplasm of these cells, and these were immunopositive for ubiquitin, nitrotyrosine and dityrosine, and positive for thioflavin S staining. Thus, the obtained cytoplasmic aggregates shared many features with inclusion bodies in synucleinopathies. The gamma-tubulin and molecular chaperones coexisted as well, suggesting that the aggregate formation is associated with the intracellular transport along microtubules and may reflect protective responses against neuronal insults. This cellular model not only will be informative for our understanding of the pathophysiological process in synucleinopathies, but also can be applied to the screening of neuroprotective molecules with therapeutic potential.
 ...
PMID:Histochemical features of stress-induced aggregates in alpha-synuclein overexpressing cells. 1503 22

Alpha-synuclein (alpha-syn) is a major component of inclusion bodies in Parkinson's disease (PD) and other synucleinopathies. To clarify the possible roles of alpha-syn in the molecular pathogenesis of neurodegenerative diseases, we have established a novel cellular model based on the differentiation of SH-SY5Y cells that overexpress alpha-syn. In the presence of ferrous iron, differentiation of the cells led to the formation of large perinuclear inclusion bodies, which developed from scattered small aggregates seen in undifferentiated cells. The iron-induced alpha-syn-positive inclusions co-localized largely with ubiquitin, and some of them were positive for nitrotyrosine, lipid, gamma-tubulin and dynein. Notably, treatment with nocodazole, a microtubule depolymerizing agent, interrupted the aggregate formation but led to a concomitant increase of apoptotic cells. Therefore, it appears that an intracellular retrograde transport system via microtubules plays a crucial role in the aggregate formation and also that the aggregates may represent a cytoprotective response against noxious stimuli. This cellular model will enable better understanding of the molecular pathomechanisms of synucleinopathy.
 ...
PMID:Accelerated alpha-synuclein aggregation after differentiation of SH-SY5Y neuroblastoma cells. 1519 67

Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitin-protein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Disease-associated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and alpha-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.
 ...
PMID:UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. 1522 95

Neurodegenerative disorders are characterized by progressive loss of specific neurons in the central nervous system. Although they have different etiologies and clinical manifestations, most of them share similar histopathologic characteristics such as the presence of inclusion bodies in both neurons and glial cells, which represent intracellular aggregation of misfolded or aberrant proteins. In Parkinson's disease, formation of inclusion bodies has been associated with the aggresome-related process and consequently with the centrosome. However, the significance of the centrosome in the neurodegenerative process remains obscure. In the present study, the morphological and functional changes in the centrosome induced by rotenone, a common insecticide used to produce experimental Parkinsonism, were examined both in vitro and in vivo. Aggregation of gamma-tubulin protein, which is a component of the centrosome matrix and recently identified in Lewy bodies of Parkinson's disease, was observed in primary cultures of mesencephalic cells treated with rotenone. Rotenone-treated neurons and astrocytes showed enlarged and multiple centrosomes. These centrosomes also displayed multiple aggregates of alpha-synuclein protein. Neurons with disorganized centrosomes exhibited neurite retraction and microtubule destabilization, and astrocytes showed disturbances of mitotic spindles. The Golgi apparatus, which is closely related to the centrosome, was dispersed in both rotenone-treated neuronal cells and the substantia nigra of rotenone-treated rats. Our findings suggested that recruitment of abnormal proteins in the centrosome contributed to the formation of inclusion bodies, and that rotenone markedly affected the structure and function of the centrosome with consequent induction of cytoskeleton disturbances, disassembly of the Golgi apparatus and collapse of neuronal cells.
 ...
PMID:Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: relevance to formation of inclusion bodies and neurodegeneration. 1589 36

Little is known about key pathological events preceding overt neuronal degeneration in Parkinson's disease (PD) and alpha-synucleinopathy. Recombinant adeno-associated virus 2-mediated delivery of mutant (A53T) human alpha-synuclein into the substantia nigra (SN) under a neuron-specific synapsin promoter resulted in protracted neurodegeneration with significant dopaminergic (DA) neuron loss by 17 weeks. As early as 4 weeks, there was an increase in a dopamine metabolite, DOPAC and histologically, DA axons in the striatum were dystrophic with degenerative bulbs. Before neuronal loss, significant changes were identified in levels of proteins relevant to synaptic transmission and axonal transport in the striatum and the SN. For example, striatal levels of rabphilin 3A and syntaxin were reduced. Levels of anterograde transport motor proteins (KIF1A, KIF1B, KIF2A, and KIF3A) were decreased in the striatum, whereas retrograde motor proteins (dynein, dynamitin, and dynactin1) were increased. In contrast to reduced levels in the striatum, KIF1A and KIF2A levels were elevated in the SN. There were dramatic changes in cytoskeletal protein levels, with actin levels increased and alpha-/gamma-tubulin levels reduced. In addition to these alterations, a neuroinflammatory response was observed at 8 weeks in the striatum, but not in the SN, demonstrated by increased levels of Iba-1, activated microglia and increased levels of proinflammatory cytokines, including IL-1beta, IFN-gamma and TNF-alpha. These results demonstrate that changes in proteins relevant to synaptic transmission and axonal transport coupled with neuroinflammation, precede alpha-synuclein-mediated neuronal death. These findings can provide ideas for antecedent biomarkers and presymptomatic interventions in PD.
 ...
PMID:Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. 1929 43


1 2 Next >>