Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems

MacInnes, Nicholas; Iravani, Mahmoud M.; Perry, Elaine K.; Piggott, Margaret A.; Perry, Robert H.; Jenner, Peter; Ballard, Clive

doi:10.1007/s00702-008-0027-6

Cited by 30 publications

(17 citation statements)

References 31 publications

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“…Thus, volume change in these structures may reflect trans-synaptic neuronal loss, consistent with previous observations in lactacystin-lesioned animals [79]. However, a role for concomitant glial cell pathology cannot be excluded.…”

Section: Discussionsupporting

confidence: 88%

Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

et al. 2011

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Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

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Section: Discussionsupporting

confidence: 88%

Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

et al. 2011

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“…Marked cholinergic deficits accompanied by inclusions positive for aSyn and Ubi suggest that proteasomal abnormalities are present in cortical LBD [64].…”

Section: Consensus Pathologic Guidelines For the Diagnosis Of Dementimentioning

confidence: 99%

Formation and development of Lewy pathology: a critical update

Jellinger¹

2009

J Neurol

171

141

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Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic alpha-synuclein (alpha Syn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with alpha Syn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of alpha Syn/LBs proposed by Braak et al. (Neurobiol Aging 24:197-211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863-1872, 2005), by semiquantitative scoring to alpha Syn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. alpha Syn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral alpha Syn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7-8.3% of those with alpha Syn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30-55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/alpha Syn pathology are to be confirmed by future studies, the currently used morphologic staging/classification systems should be revised accordingly.

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“…Additional molecular alterations converge in the pathogenesis of DLB, including impaired autophagy and ubiquitin-proteasome system of protein (46–50), as well as altered responses to protein misfolding (51). Preliminary studies have shown impaired mitochondrial activity and oxidative damage involving proteins, lipids, and DNA in the neocortex in DLB (52, 53); α-synuclein is one of the targets of oxidative damage in the frontal cortex in DLB (54).…”

Section: Introductionmentioning

confidence: 99%

Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

et al. 2017

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ObjectivesThe goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology.MethodsReal-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used.ResultsThe main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer’s disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1–40 and β-amyloid 1–42, and increased TNFα mRNA and protein expression, distinguish rpDLB.ConclusionMolecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

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Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems

Cited by 30 publications

References 31 publications

Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

Evolution of Extra-Nigral Damage Predicts Behavioural Deficits in a Rat Proteasome Inhibitor Model of Parkinson's Disease

Formation and development of Lewy pathology: a critical update

Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms

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