Phosphorylation of tau and α-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related α-synucleinopathies

Muntané, Gerard; Dalfó, Esther; Martínez, A.; Ferrer, Isidró

doi:10.1016/j.neuroscience.2008.01.030

Cited by 130 publications

(61 citation statements)

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“…Tau phosphorylation was found in synapseenriched fractions of frontal cortex in PD and AD [355] and in brainstem of AS mice [591] and EO familial DLB shows extensive tau pathology [592]. …”

Section: α-Synuclein and Protein Interactionsmentioning

confidence: 99%

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The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…Tau phosphorylation was found in synapseenriched fractions of frontal cortex in PD and AD [355] and in brainstem of AS mice [591] and EO familial DLB shows extensive tau pathology [592]. …”

Section: α-Synuclein and Protein Interactionsmentioning

confidence: 99%

“…Expression of pAS in the brain is very low under normal conditions and is undetectable by immunohistochemical methods, but is increased in PD, DLB and AD with LB pathology [355]. It is the most prominent species of AS isolated from postmortem brains with LB disease [118].…”

Section: α-Synuclein and Neurodegenerationmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…While aSyn phosphorylated at serine 129 (paSyn) is predominant in LB disorders [4,91], Ab deposition in cerebral cortex promotes accumulation of both aSyn and tau [73]. Tau phosphorylation at Ser396 has been observed in synaptic-enriched fractions of the frontal cortex in PD and DLB and in advanced stages of AD [72], and genetic variation of aSyn has been shown to modulate neurofibrillary tau pathology [79]. This suggests that aSyn and tau may be related to several pathologic processes (bystander effect), which may explain the frequent overlap between synucleinopathies and tauopathies [31,58].…”

Section: Formation Of Lewy Bodiesmentioning

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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“…3C). The combination of Lewy bodies and Lewy neurites is sometimes referred to as Lewy-related pathology (Dickson et al 2009), because it is increasingly clear that abnormal a-synuclein accumulation in neuronal perikarya may be the tip of the iceberg, with evidence of accumulation not only in neuronal cell processes (Irizarry et al 1998), but also with the synaptic compartment (Muntane et al 2008;Schulz-Schaeffer 2010).…”

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confidence: 99%

Parkinson's Disease and Parkinsonism: Neuropathology

Dickson¹

2012

Cold Spring Harbor Perspectives in Medicine

655

526

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Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein a-synuclein or the microtubule binding protein tau. In idiopathic Parkinson's disease (PD), a-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major a-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of a-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, a-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.

show abstract

Phosphorylation of tau and α-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related α-synucleinopathies

Cited by 130 publications

References 64 publications

The role of α-synuclein in neurodegeneration — An update

The role of α-synuclein in neurodegeneration — An update

Formation and development of Lewy pathology: a critical update

Parkinson's Disease and Parkinsonism: Neuropathology

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