Disease relevance of Lewy Bodies

• Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease [1].
• Immunohistochemical examination of 20 Down's syndrome brains, using antibodies to alpha-, beta-, and gamma-synuclein, demonstrated many alpha-synuclein-positive Lewy bodies and dystrophic neurites in 50% of amygdala samples from Down's syndrome brains with Alzheimer's disease [2].
• Autopsy of a 73-year-old patient, who carried two mutant Parkin alleles (delExon7 + del1072T), showed PD-type cell loss, reactive gliosis, and alpha-synuclein-positive Lewy bodies in the substantia nigra and locus ceruleus [3].
• Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS [4].
• The expression of alpha-synuclein, a synaptic molecule implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body disease is increased upon injury to the nervous system, indicating that it might play a role in regeneration and plasticity; however, the mechanisms are unclear [5].

Psychiatry related information on Lewy Bodies

• Intracytoplasmic filamentous aggregates, such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, are composed of the proteins tau and alpha-synuclein, respectively [6].
• INTERPRETATION: Rivastigmine 6-12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually [7].
• Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples [8].
• In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions [9].
• Coexistence of Pick bodies and atypical Lewy bodies in the locus ceruleus neurons of Pick's disease [10].

High impact information on Lewy Bodies

• Alpha-synuclein is present in Lewy bodies of patients with sporadic PD, suggesting that alpha-synuclein may be involved in the pathogenesis of PD [11].
• The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies [1].
• With the dopaminergic presynaptic ligand FP-CIT and single photon emission tomography we have shown a severe dopaminergic degeneration in a patient with a necropsy confirmed diagnosis of dementia with Lewy bodies (DLB) [12].
• Parkinson's disease, but not Alzheimer's disease, Lewy body variant associated with mutant alleles at cytochrome P450 gene [13].
• Tacrine for senile dementia of Alzheimer's or Lewy body type [14].

Chemical compound and disease context of Lewy Bodies

• Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies [15].
• Recent studies have shown that the neurodegenerative process in disorders with Lewy body formation, such as Parkinson's disease and dementia with Lewy bodies, is associated with alpha-synuclein accumulation and that beta-synuclein might protect the central nervous system from the neurotoxic effects of alpha-synuclein [16].
• CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA [17].
• Dementia with Lewy bodies: response of delirium-like features to donepezil [18].
• Iodine-123 iodobenzamide single-photon emission computed tomography in dementia with Lewy bodies seems promising [19].

Biological context of Lewy Bodies

• This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation [20].
• Although candidate gene approaches to linkage in PD families have not been rewarding, a genome wide scan mapped PD to 4q21-23 in one large family with PD with diffuse Lewy bodies, where a candidate gene, alpha-synuclein, resides [21].
• Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease [22].
• A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death [23].
• This observation suggests that cdk5 might be a protein kinase involved in the phosphorylation of a molecular component of Lewy bodies, for example, neurofilament proteins known to be present in these inclusions [24].

Anatomical context of Lewy Bodies

• Finally, colocalization of alpha-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD [25].
• The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites [26].
• 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 [27].
• Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra and the presence of cytoplasmic inclusions known as Lewy bodies (LBs) [28].
• There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects [29].

Associations of Lewy Bodies with chemical compounds

• In view of proteolytic degradation, we have found that the serine protease neurosin (kallikrein-6) degrades alpha-synuclein and co-localizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions [30].
• The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects [29].
• There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects [29].
• Lewy body proteins were resolved by polyacrylamide gel electrophoresis [31].
• No significant changes in substance P content were observed in incidental Lewy body disease [32].

Gene context of Lewy Bodies

• Our results indicate that ubiquilin may be an important modulator of presenilin protein accumulation and that ubiquilin protein is associated with neuropathological neurofibrillary tangles and Lewy body inclusions in diseased brain [33].
• 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 [27].
• We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of alpha-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques [34].
• The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure-pathogenesis relationship for the gene product of LRRK2 [35].
• Many PNMT-positive neurons contained Lewy bodies [36].

Analytical, diagnostic and therapeutic context of Lewy Bodies

• Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD [37].
• Immunoblotting confirmed the presence of MAP-1B and alpha-synuclein in purified Lewy bodies [31].
• Double immunofluorescence labeling and confocal microscopy revealed approximately 80% of cortical Lewy bodies contained microtubule-associated protein 1B (MAP-1B) that overlapped with alpha-synuclein [31].
• An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model [38].
• Electron microscopy occasionally showed an intimate relationship between the paired helical filaments of the neurofibrillary tangle and Lewy bodies in nerve cell processes in the hypothalamus [39].

References