Dementia with Lewy bodies in an elderly Greek male due to α-synuclein gene mutation

Morfis, Litsa; Cordato, Dennis

doi:10.1016/j.jocn.2005.11.040

Cited by 29 publications

(19 citation statements)

References 14 publications

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“…The exact biological function of LRRK2 remains largely unclear and how its mutations lead to neurodegeneration is not known, but protein modifications from altered phosphorylation could lead to misfolding and aggregation of the target protein [278]. Therefore, increasing Three single point mutations in AS were found to be associated with EOPD: Ala53Thr (A53T), identified in a large Italian family (Contursi) [280] and in Greek kindreds [281][282][283][284], showing both AS and tau pathology [285], The A53T mutation was also found in diffuse DLB (DDLB) [286,287], while the relevance of DJ-1 mutation for DLB is not known. Ala30Pro (A30P), in a German kindred [288], shows similarities to PD but more severe pathology [289], and E46K or Glu46Lys [295].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

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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Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…Fibrillar forms of the pre-synaptic protein, alphasynuclein, are the major protein component of these inclusions, and are invariably colocalized with ubiquitin (Spillantini et al 1997(Spillantini et al , 1998. Mutant alpha-synuclein has an increased propensity to aggregate, and a number of mutations in the alpha-synuclein gene cause familial PD (reviewed in Gasser 2007), and DLB (Zarranz et al 2004; Morfis and Cordato 2006). Evidence suggests that failed degradation of alpha-synuclein, by the ubiquitin proteosome system (UPS), leads to its aggregation, ultimately contributing to Lewy body formation.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Upregulation of Endogenous Alpha-Synuclein Precedes Ubiquitination in Cultured Dopaminergic Neurons

2010

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α-Synuclein is the major protein component of Lewy bodies--the pathological hallmark of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Its accumulation into intracellular aggregates is implicated in the process of Lewy body formation. However, its roles in both normal function, and disease, remain controversial. Using a novel model of chronic oxidative stress in cultured dopaminergic and cortical neurons, we report that endogenous α-synuclein is upregulated in response to low dose toxicity. This response is conserved between subpopulations of cortical and dopaminergic neurons, and confers relative resistance to apoptosis following secondary insult. Additional acute oxidative stress leads to intracellular accumulation of α-synuclein. These punctate deposits colocalize with ubiquitin, which is central to proteosome-mediated protein degeneration, and is the second major component of Lewy bodies. The current results imply that differential levels of α-synuclein expression may influence neuronal vulnerability in chronic neurodegenerative diseases. They further support a 'two hit' hypothesis for Lewy body formation, whereby mild stress causes a protective upregulation of α-synuclein. However, such increased levels of α-synuclein may drive its accumulation, following additional toxic insult. Finally, these results support a common mechanism for degeneration of dopaminergic and cortical neurons, affected in PD, and DLB, respectively.

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“…SNCA point mutations [9][10][11] and whole gene multiplications [12,13] have been repeatedly associated with clinical and pathologic phenotypes ranging from PD to PDD and DLB. These discoveries highlight the direct role of -synuclein overexpression in the pathogenesis of LB disorders and strongly support the view that PD and DLB are parts of the same pathologic spectrum [13][14][15].…”

Section: -Synuclein Mutationsmentioning

confidence: 99%

“…SNCA duplications seem more often associated with classic PD [14,15], whereas triplications seem more often responsible for PDD and DLB [12,13]. Furthermore, the missense mutation A30P is found in association with typical PD [16], whereas E46K and A53T are associated with PD, PDD, or DLB in different patients [9][10][11]17].…”

Section: -Synuclein Mutationsmentioning

confidence: 99%

Recent advances in the genetics of dementia with Lewy bodies

Bonifati

2008

Curr Neurol Neurosci Rep

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In the past few years, mutations have been identified in the genes encoding alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in some patients with dementia with Lewy bodies (DLB). Furthermore, a novel locus for familial DLB has been mapped to chromosome 2q35-q36. Collectively, these discoveries highlight a substantial overlap between the known genetic determinants of Parkinson's disease and DLB, as well as the presence of profound etiologic heterogeneity in Lewy body disorders.

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Dementia with Lewy bodies in an elderly Greek male due to α-synuclein gene mutation

Cited by 29 publications

References 14 publications

The role of α-synuclein in neurodegeneration — An update

The role of α-synuclein in neurodegeneration — An update

Neuroprotective Upregulation of Endogenous Alpha-Synuclein Precedes Ubiquitination in Cultured Dopaminergic Neurons

Recent advances in the genetics of dementia with Lewy bodies

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