Alpha‐synuclein and Parkinson's disease: Implications from the screening of more than 1,900 patients

Berg, Daniela; Niwar, Marc; Maaß, Sylvia; Zimprich, Alexander; Möller, J. Carsten; Wuellner, Ullrich; Schmitz‐Hübsch, Tanja; Klein, Christine; Tan, Eng King; Schöls, Lüdger; Marsh, Laura; Dawson, Ted M.; Janetzky, Bernd; Müller, Thomas; Woitalla, Dirk; Kostić, Vladimir; Pramstaller, Peter P.; Oertel, Wolfgang H.; Bauer, Peter; Krueger, Rejko; Gasser, Thomas; Rieß, Olaf

doi:10.1002/mds.20504

Cited by 68 publications

(38 citation statements)

References 11 publications

(17 reference statements)

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“…The first PD mutation was identified in 1997, in a large kindred of Italian/American origin and three unrelated Greek families, all with autosomal dominant inheritance [178]. Two other extremely rare [187] missense mutations have been identified [188,189]. In the Italian/American kindred, the disease was typical for PD with neuronal loss in the substantia nigra and Lewy bodies, but relatively early onset, rapid course and less tremor [190].…”

Section: Genes Associated With Autosomal Dominant Pdmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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Section: Genes Associated With Autosomal Dominant Pdmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…The presence of Lewy bodies and Lewy neurites in substantia nigra is a common finding in patients with PD; the major filamentous protein component of the LBs and LNs is a-synuclein (Spillantini et al 1998). Mutations in the a-synuclein gene lead to early-onset autosomal-dominant forms of inherited PD associated with the accumulation of a-synuclein aggregates in humans, providing a strong link to the disease (Polymeropoulos et al 1997;Kruger et al 1998;Dawson and Dawson 2003a,b;Berg et al 2005). Accumulation of misfolded proteins can occur when an imbalance develops between the factors tending to promote protein unfolding (oxidant stress, pH stress, thermal shock, prion-mediated disruption) and the systems responsible for removal (ubiquitinylation, proteasomes) or refolding (molecular chaperones).…”

Section: Reconciliation With Current Models Of Pd Pathogenesismentioning

confidence: 99%

Physiological Phenotype and Vulnerability in Parkinson's Disease

Surmeier

Guzmán²,

Sánchez³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

102

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This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype-how a neuron generates and regulates action potentials-makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca 2þ entry, and modest intrinsic Ca 2þ buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this atrisk phenotype is created by Ca 2þ entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible.

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“…What is more important is the realization that aggregation of ␣-synuclein plays critical roles in sporadic PD (3,6,7). The precise mechanisms by which ␣-synuclein mediates PD development remain to be defined, although it appears that the following processes are involved at least partially: increased oxidative stress, mitochondrial dysfunction, and abnormal protein aggregation (␣-synuclein in particular) as well as failure of the ubiquitin-proteasome system and lysosomal system (8,9).…”

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Identification of Novel Proteins Associated with Both α-Synuclein and DJ-1

Jin

Davis

et al. 2007

Molecular & Cellular Proteomics

172

138

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The molecular mechanisms leading to neurodegeneration in Parkinson disease (PD) remain elusive, although many lines of evidence have indicated that ␣-synuclein and DJ-1, two critical proteins in PD pathogenesis, interact with each other functionally. The investigation on whether ␣-synuclein directly interacts with DJ-1 has been controversial. In the current study, we analyzed proteins associated with ␣-synuclein and/or DJ-1 with a robust proteomics technique called stable isotope labeling by amino acids in cell culture (SILAC) in dopaminergic MES cells exposed to rotenone versus controls. We identified 324 and 306 proteins in the ␣-synuclein-and DJ-1-associated protein complexes, respectively. Among ␣-synuclein-associated proteins, 141 proteins displayed significant changes in the relative abundance (increase or decrease) after rotenone treatment; among DJ-1-associated proteins, 119 proteins displayed significant changes in the relative abundance after rotenone treatment. Although no direct interaction was observed between ␣-synuclein and DJ-1, whether analyzed by affinity purification followed by mass spectrometry or subsequent direct co-immunoprecipitation, 144 proteins were seen in association with both ␣-synuclein and DJ-1. Of those, 114 proteins displayed significant changes in the relative abundance in the complexes associated with ␣-synuclein, DJ-1, or both after rotenone treatment. A subset of these proteins (mortalin, nucleolin, grp94, calnexin, and clathrin) was further validated for their association with both ␣-synuclein and DJ-1 using confocal microscopy, Western blot, and/or immunoprecipitation. Thus, we not only confirmed that there was no direct interaction between ␣-synuclein and DJ-1 but also, for the first time, report these five novel proteins to be associating with both ␣-synuclein and DJ-1. Further characterization of these docking proteins will likely shed more light on the mechanisms by which DJ-1 modulates the function of ␣-synuclein, and vice versa, in the setting of PD.

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Alpha‐synuclein and Parkinson's disease: Implications from the screening of more than 1,900 patients

Cited by 68 publications

References 11 publications

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Physiological Phenotype and Vulnerability in Parkinson's Disease

Identification of Novel Proteins Associated with Both α-Synuclein and DJ-1

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