Molecular Pathology of Lewy Body Diseases

Beyer, Katrin; Domingo-Sàbat, Montserrat; Ariza, Aurelio

doi:10.3390/ijms10030724

Cited by 102 publications

(86 citation statements)

References 144 publications

(216 reference statements)

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“…17 The reasons for the loss of parv-ir, and its effect on the fast-spiking firing properties in hippocampal interneurons are unknown, but a compensatory homeostatic mechanism to try to restore normal network activity has recently been proposed. 42 Besides the well-documented, profound impairments of protein degradation in DLB, 43 which might contribute to cell loss in DLB, 44 there is increasing evidence in favour of mitochondrial DNA deletions and mutations in genes coding for mitochondrial proteins as important pathologic factors in alpha-synuclein pathology and Parkinsonism 26,43 and others. These changes might contribute to increasing oxidative stress in DLB and related neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 97%

Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies

et al. 2011

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Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB. However, elevated parv levels are found in the cerebrospinal fluid of patients suffering from dementia with Lewy bodies. We performed an immunohistochemical analysis of hippocampal parv-immunoreactive neurons in well-characterised DLB cases and from controls using a specific antibody against the calcium binding protein. In addition, an analysis of the regional and cellular distribution of alpha-synuclein was carried out. Subfield and laminar distribution of parv-immunoreactive (ir) neurons on the hippocampus in subjects with DLB and controls were present exclusively as non-granule cells of the dentate gyrus (DG)/hilus and non-pyramidal cells of CA1, CA2, CA3 and CA4 areas of the hippocampus. The distribution patterns did not differ qualitatively between DLB and controls. Quantitative estimation of parv-ir neuron density revealed significant decreases in the dentate (DG)/hilus region as well as in the CA1 subfield. Double immunolabelling experiments showed that only 2% of parv expressing interneurons were laden with alpha-synuclein immunoreactive material. No significant changes were found for the total neuron densities in DLB cases. Our results show a partial loss of parv-expressing hippocampal interneurons in DLB, which might be the result of long-lasting calcium overload in combination with a proposed impaired mitochondrial function. It remains to be elucidated if the numerical decrease of this particular subset of hippocampal interneurons has consequences for the gamma (20-80 Hz) frequency activity in DLB patients.

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Section: Discussionmentioning

confidence: 97%

Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies

et al. 2011

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“…PDD is distinguished from PD by the additional presence of Lewy bodies [LBs] in the frontal gyrus (Mattila et al, 2000), which are primarily composed of α-Syn inclusions, and aggregation of the latter is thought to be a key pathogenic event in formation of LBs (Beyer et al, 2009). In addition to aggregation of α-Syn, thought to the first step in formation of LBs, impairment of protein degradative pathways, including both the ubiquitin-proteasome system and the autophagy-lysosomal pathway, are also believed to play an important role during the development of LBs (Beyer et al, 2009). In IFG of both PD and PDD, the diminished proteasomal activity we observe as a consequence of decreased 19S and 20S subunits of the proteasome, may lead to increased accumulation of α-Syn, but which in the absence of oxidative stress and p-GSK-3β, does not lead to any Tauopathic changes.…”

Section: Discussionmentioning

confidence: 99%

Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia

Wills

Jones

Haggerty

et al. 2010

Experimental Neurology

173

172

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Parkinson’s disease [PD], a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein [α-Syn] in dopaminergic neurons. Here we examined tauopathic changes and the α-Syn/p-GSK-3β/proteasome pathway in postmortem striata and inferior frontal gyri [IFG] from patients with PD and PD with dementia [PDD]. In both PD and PDD, α-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble α-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3β phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of α-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3β in IFG. Unlike Alzheimer’s disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.

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“…Studies in cell systems have established that ␣-Syn aggregation is potentiated through interaction with Sph1 (23,50,54). Concordantly, post mortem brain examinations have demonstrated that both Sph1 and ␣-Syn are major molecular components of Lewy bodies found in ␣-synucleinopathies (25,50). In this study, we identified for the first time that Sph1 interacts with the heterodimeric complex that comprises PtdIns(3,5)P 2 5-phosphatase Sac3 and the scaffolding protein ArPIKfyve in both neuronal and non-neuronal cells (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…To this end, here we undertook a proteomic screen of mouse brain lysates using the ArPIKfyveSac3 complex as bait and unraveled ␣-synuclein-interacting protein Synphilin-1 (Sph1) (gene symbol SNCAIP) as a new interaction partner of the ArPIKfyve-Sac3 complex. Sph1, a predominantly neuronal protein that promotes aggregation of ␣-synuclein (␣-Syn) (gene symbol SNCA), is a major component of inclusion bodies, or Lewy bodies, found in post mortem brain samples of neurodegenerative ␣-synucleinopathies such as Parkinson's and Lewy body dementia (23)(24)(25)(26)(27). We further report that the ArPIKfyve-Sac3 complex has a profound ability to reduce the aggregation potential of Sph1 and shift the aggregated protein toward the soluble form.…”

mentioning

confidence: 90%

The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation

Ikonomov

Sbrissa

Compton

et al. 2015

Journal of Biological Chemistry

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Background:The cytosolic ArPIKfyve-Sac3 complex binds PIKfyve to regulate housekeeping endosomal functions but other tissue-specific interactors and functions are unknown. Results: Brain Synphilin-1 is a novel interaction partner of the ArPIKfyve-Sac3 complex. Conclusion:The ArPIKfyve-Sac3 complex is an effective inhibitor of aggregate formation by Synphilin-1. Significance: The novel molecular means for reducing cytoplasmic aggregates of Synphilin-1 provides new insights into neurodegeneration mechanisms.

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Molecular Pathology of Lewy Body Diseases

Cited by 102 publications

References 144 publications

Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies

Partial loss of parvalbumin-containing hippocampal interneurons in dementia with Lewy bodies

Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia

The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation

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