Lewy body-related α-synucleinopathy in aging

Saito, Yoko; Ruberu, Nyoka N.; Sawabe, Motoji; Arai, Tomio; Kazama, Hirohito; Hosoi, Takayuki; Yamanouchi, Hiroshi; Murayama, Shigeo

doi:10.1016/j.parkreldis.2006.05.023

Cited by 10 publications

(14 citation statements)

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“…Classic PD is manifested as a complex motor disorder that results from the reduced dopaminergic input of the substantia nigra to the striatum and the resultant altered basal ganglia modulation of motor control (4). Cases with Lewy body pathology in the brain stem without motor symptoms are considered as having incidental PD (iPD) because they are unexpectedly discovered after appropriate postmortem neuropathological study (5)(6)(7)(8). Whether these cases constitute premotor PD has been a matter of controversy for some years, because it cannot be confirmed that these cases would have progressed to Parkinsonism if they had survived longer.…”

Section: Introductionmentioning

confidence: 99%

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Fabelo

Martín

Santpere

et al. 2011

Mol Med

317

253

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Lipid rafts are cholesterol-and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Fabelo

Martín

Santpere

et al. 2011

Mol Med

317

253

View full text Add to dashboard Cite

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“…(2) Regarding the nigrostriatal or mesolimbic dopamine pathway, α-syn-positive neurons were increasingly It is generally accepted that in neuropathological conditions, phosphorylated α-syn abnormally accumulates within the cytoplasm and aggregates to form insoluble fibrils characterized by the intracellular inclusion LB [5]. This α-syn-related event termed synucleinopathy is widely involved not only in PD, PDD, and DLB, but also in multiple system atrophy and part of Alzheimer's disease (AD) [7,8,28,29]. In order to understand the progress in synucleinopathy, it is essential to study how α-syn-positive neurons propagate during normal aging by using nonhuman primates.…”

Section: Discussionmentioning

confidence: 99%

“…This might be explained by considering that the α-syn pathology of these structures is linked not only with the mesolimbic dopamine system, but also probably with the development in dementia-related diseases. With respect to the human brain pathology of dementia-related diseases, especially PDD, DLB, and part of AD, it has been documented that LB formation is observed primarily in the hippocampus, the amygdala, and the temporal lobe [8]. Although the Braak's hypothesis [31] is generally adopted for pathological progression of PD based on LB formation, only PD cases without dementia are dealt in this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Although the Braak's hypothesis [31] is generally adopted for pathological progression of PD based on LB formation, only PD cases without dementia are dealt in this hypothesis. The stage classification of PD has been extended with dementia cases included [8]. This describes that the LB pathology originates from the olfactory bulb and spreads to the amygdala and the temporal lobe.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, α-syn accumulation in the hippocampus and the amygdala develops the pathology of PDD and DLB. Similarly, the α-syn accumulation therein is exhibited in part of AD, leading to cognitive declines [8].…”

Section: Discussionmentioning

confidence: 99%

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Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

Kimura

Inoue

Kuroiwa

et al. 2017

Journal of the Neurological Sciences

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In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.

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When does Parkinson's disease begin?

2009

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Pathological and neuroimaging studies have shown that in Parkinson's disease (PD) there is a "subclinical" or "premotor" period during which dopaminergic neurons in the substantia nigra (SN) degenerate but typical motor symptoms have not yet developed. Post-mortem studies based on nigral cell counts and evaluating dopamine levels in the striata, and imaging studies assessing the nigrostriatal pathway in vivo, have estimated that this time period could last 3 to 6 years. In addition, emerging evidence indicates that the neuropathological process of PD does not start in the SN but more likely elsewhere in the nervous system: in the lower brainstem and the olfactory bulb, or even more distant from the SN, such as in the peripheral autonomic nervous system. Patients with PD frequently can present non-motor symptoms, such as hyposmia or constipation, years before the development of classical motor signs. The physiopathology of these "premotor" symptoms, though still unclear, is currently thought to be related to early involvement by the pathological process underlying PD of non-dopaminergic lower brainstem structures or autonomic plexuses. However, the answer to the question "when does PD start" remains uncertain. Here, we review clinical, pathological, and neuroimaging data related to the onset of the pathological process of PD, and propose that its onset is non-motor and that non-motor symptoms could begin in many instances 10 and 20 years before onset of motor symptoms. The variable course of the disorder once the motor symptoms develop, suggests that the start and progression of premotor PD is also highly variable and given the heterogeneous nature of PD, may differ depending on the cause/s of the syndrome. When and where the neuropathological process develops in PD remains uncertain.

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Lewy body-related α-synucleinopathy in aging

Cited by 10 publications

References 0 publications

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

When does Parkinson's disease begin?

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