Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease

Mattila, P. M.; Rinne, Juha O.; Helenius, Hans; Dickson, Dennis W.; Röyttä, Matias

doi:10.1007/s004019900168

Cited by 312 publications

(219 citation statements)

References 31 publications

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“…This notion is supported by studies showing that the density of ␣-syn pathological inclusions correlates with disease severity in demented PD and DLB patients (62)(63)(64)(65)(66). Moreover, transgenic mouse models suggest that ␣-syn inclusions impair cellular function by obstructing normal cellular trafficking and disrupting cell morphology (44,67).…”

Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 84%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

346

317

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The identification of a novel mutation (E46K) in one of the KTKEGV-type repeats in the amino-terminal region of ␣-synuclein suggests that this region and, more specifically, Glu residues in the repeats may be important in regulating the ability of ␣-synuclein to polymerize into amyloid fibrils. It was demonstrated that the E46K mutation increased the propensity of ␣-synuclein to fibrillize, but this effect was less than that of the A53T mutation. The substitution of Glu 46 for an Ala also increased the assembly of ␣-synuclein, but the polymers formed can have different ultrastructures, further indicating that this amino acid position has a significant effect on the assembly process. The effect of residue Glu 83 in the sixth repeat of ␣-synuclein, which lies closest to the amino acid stretch critical for filament assembly, was also studied. Mutation of Glu 83 to a Lys or Ala increased polymerization but perturbed some of the properties of mature amyloid. These results demonstrated that some of the Glu residues within the repeats can have significant effects on modulating the assembly of ␣-synuclein to form amyloid fibrils. The greater effect of the A53T mutation, even when compared with what may be predicted to be a more dramatic mutation such as E46K, underscores the importance of protein microenvironment in affecting protein structure. Moreover, the relative effects of the A53T and E46K mutations are consistent with the age of onset of disease. These findings support the notion that aberrant ␣-synuclein polymerization resulting in the formation of pathological inclusions can lead to disease.

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Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 84%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

346

317

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“…Many PD patients have substantial load of Alzheimer's histopathological features [15,17,48,49]. There is evidence that dementia in PD is associated more closely with cortical deposition of the hallmark component of Lewy bodies, α-synuclein, than with Alzheimer's pathology [2,43,68], although this conclusion is disputed by some authors [82]. A strong correlation between frequency of plaques and neurofibrillary tangles with neocortical Lewy bodies has been reported [4], suggesting common origin and/or cooperativity between the two types of pathology.…”

Section: Introductionmentioning

confidence: 99%

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

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Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

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“…However, molecular pathological alterations are also linked with the incidence of cognitive deficiency in PD. Mattila et al has documented a study, where α-synuclein aggregation and Lewy body formations were reported to be highly correlated with cognitive impairment in PD [37].…”

Section: Reviewmentioning

confidence: 95%

Cognitive and Psychological Anomalies in Parkinsons Disease: An Insight into Non-Motor Characteristic Features

Choudhury¹,

Rao²,

R³

et al. 2017

Neuropsychiatry

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While most of the clinical concerns for Parkinson's disease (PD) are limited to the cardinal motor abnormalities, non-motor features like cognitive and psychological anomalies are also acquired ample of importance in last few decades. Progressive research has showcased several obvious incidences of cognitive and psychological anomalies in the pathophysiology of PD. It has been reported that, almost 30% PD sufferers show different degree of cognitive impairment but lack of awareness or negligence makes it difficult to diagnose it, at the initial stage of the disease. As a result, cognitive and psychological impairments continue to increases progressively and deteriorate the quality of life of the patient. It is presumable that, early detection of PD can be achieved by the identification of specific set of cognitive and psychological anomalies and the similar scope might open up new avenue in the non-invasive diagnosis of PD. In the present review, we have accumulated all the timely documentation on cognitive and psychological anomalies in PD and highlighted most of the non-motor features with rational justification for the relevance of their study in the early diagnosis of PD.

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Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease

Cited by 312 publications

References 31 publications

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Cognitive and Psychological Anomalies in Parkinsons Disease: An Insight into Non-Motor Characteristic Features

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