Mutated α-synuclein gene in two Greek kindreds with familial PD: Incomplete penetrance?

Papadimitriou, Alexandros; Veletza, V.; Hadjigeorgiou, George; Patrikiou, A.; Hirano, Minoru; Anastasopoulos, I.

doi:10.1212/wnl.52.3.651

Cited by 132 publications

(74 citation statements)

References 9 publications

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“…This mutation was latter reported in other families with the same holotype, supporting the possibility of a common Mediterranean ancestral [63,64].…”

Section: Autosomic Dominant Forms Of Parkinson Diseasesupporting

confidence: 76%

Genes involved in the development of Parkinson

Teixeira¹,

Cardoso²

2017

Open J Parkinsons Dis Treatm

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Background: Parkinson's disease is the second most important neurodegenerative disorder, affecting 3% of individuals older than 80 years of age. Main clinical symptoms are resting tremor, postural instability, bradykinesia and rigidity, with a good response to levodopa therapy. Purpose of the study:The main goal of this work is to make a deep analysis on the genetic factors and kind of heritage involved in the development of Parkinson. Main fi ndings:Over the last years, numerous studies allowed to confirm the unquestionable contribution of genetic factors to the complex pathogenesis of this disease. Highly penetrant mutations producing rare, monogenic forms of the disease have been identifi ed in singular genes such as SNCA, Parkin, DJ-1, PINK1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA genes were identifi ed as strong risk factors for Parkinson's disease in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for Parkinson's disease.Investigating Mendelian forms of Parkinson disease has provided precious insight into the pathophysiology that underlies the more common idiopathic form of this disorder. Conclusions:The challenge over the next decade will be to get more data that strengthens the already available knowledge concerning genetics on Parkinson's disease, through the discovery of biological consequences of risk variants. Moreover, it is also expected that the advent of genome-wide association studies and the implementation of new research technologies will help in the identifi cation of novel risk variants for the sporadic forms of Parkinson disease.

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“…This mutation was latter reported in other families with the same holotype, supporting the possibility of a common Mediterranean ancestral [63,64].…”

Section: Autosomic Dominant Forms Of Parkinson Diseasesupporting

confidence: 76%

Genes involved in the development of Parkinson

Teixeira¹,

Cardoso²

2017

Open J Parkinsons Dis Treatm

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“…Thereafter, the A53T mutation was identified in an additional eight kindreds (11)(12)(13)(14). Another autosomal dominant mutation (A30P) in ␣-syn has been identified in a German kindred (15).…”

Section: ␣-Synmentioning

confidence: 99%

“…Interestingly, the in vitro findings of the effects of the A53T and E46K mutations on ␣-syn polymerization are consistent with pathogenesis in human subjects. Patients with the A53T mutation have an earlier age of disease onset (average age of onset, 45 years) (10,13,14,55,56) than those carrying the E46K mutation (average age of onset, 60 years) (18).…”

Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 99%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

344

309

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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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“…The neuronal presynaptic protein ␣-synuclein is a conspicuous component of intraneuronal inclusions of Lewy bodies (LBs) 1 and Lewy neurites (3)(4)(5)(6)(7)(8)(9)(10)(11), two prominent pathological features of Parkinson's disease (PD). Mutations in ␣-synuclein have been linked to familial PD (12)(13)(14), and these mutations appear to cause biophysical changes in these proteins that accelerate their fibrillogenesis in vitro (15)(16)(17)(18). However, LBs and Lewy neurites in sporadic PD and dementia with LBs (3-11) as well as glial cytoplasmic inclusions (GCIs) in multiple system atrophy (19 -23) contain filaments formed by wild-type ␣-synuclein.…”

mentioning

confidence: 99%

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

Souza¹,

Giasson²,

Chen³

et al. 2000

Journal of Biological Chemistry

529

219

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Intracellular proteinaceous aggregates are hallmarks of many common neurodegenerative disorders, and recent studies have shown that ␣-synuclein is a major component of several pathological intracellular inclusions, including Lewy bodies in Parkinson's disease (PD) and glial cell inclusions in multiple system atrophy. However, the molecular mechanisms underlying ␣-synuclein aggregation into filamentous inclusions remain unknown. Since oxidative and nitrative stresses are potential pathogenic mediators of PD and other neurodegenerative diseases, we asked if oxidative and/or nitrative events alter ␣-synuclein and induce it to aggregate. Here we show that exposure of human recombinant ␣-synuclein to nitrating agents (peroxynitrite/CO 2 or myeloperoxidase/H 2 O 2 /nitrite) induces formation of nitrated ␣-synuclein oligomers that are highly stabilized due to covalent cross-linking via the oxidation of tyrosine to form o,o-dityrosine. We also demonstrate that oxidation and nitration of pre-assembled ␣-synuclein filaments stabilize these filaments to withstand denaturing conditions and enhance formation of SDS-insoluble, heat-stable high molecular mass aggregates. Thus, these data suggest that oxidative and nitrative stresses are involved in mechanisms underlying the pathogenesis of Lewy bodies and glial cell inclusions in PD and multiple system atrophy, respectively, as well as ␣-synuclein pathologies in other synucleinopathies.Accumulations of proteinaceous fibrils are a common neuropathological feature of several different sporadic and hereditary neurodegenerative diseases (1, 2). The neuronal presynaptic protein ␣-synuclein is a conspicuous component of intraneuronal inclusions of Lewy bodies (LBs) 1 and Lewy neurites (3-11), two prominent pathological features of Parkinson's disease (PD). Mutations in ␣-synuclein have been linked to familial , and these mutations appear to cause biophysical changes in these proteins that accelerate their fibrillogenesis in vitro (15-18). However, LBs and Lewy neurites in sporadic PD and dementia with LBs (3-11) as well as glial cytoplasmic inclusions (GCIs) in multiple system atrophy (19 -23) contain filaments formed by wild-type ␣-synuclein. Moreover, high molecular mass aggregates of wild-type ␣-synuclein that are resistant to strong denaturing conditions have been recovered from purified LBs and GCIs, (4, 22-24), suggesting that covalently modified ␣-synuclein may be predisposed to form these inclusions. However, the precise molecular alterations of wild-type ␣-synuclein that lead to the formation of aggregates in these diseases are unknown.Oxidative stress has been implicated in pathogenic mechanisms of PD and many other neurodegenerative diseases (25)(26)(27). Both analytical and immunological methodologies have revealed the presence of oxidized and nitrated proteins in a number of neurodegenerative disorders (27-32), supporting a role for oxidants and nitrating agents in the development of these diseases. Moreover, ␣-synuclein inclusions in brains from patients with PD (28), ...

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Mutated α-synuclein gene in two Greek kindreds with familial PD: Incomplete penetrance?

Cited by 132 publications

References 9 publications

Genes involved in the development of Parkinson

Genes involved in the development of Parkinson

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

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