The role of α-synuclein in neurodegenerative diseases

Bennett, Michael

doi:10.1016/j.pharmthera.2004.10.010

Cited by 194 publications

(143 citation statements)

References 206 publications

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“…Alpha-synuclein (SNCA) is now considered to play a key role in the pathogenesis of PD and related synucleinopathies (see review [2]). SNCA transcription is significantly reduced (see Table 2) in the parkinsonian SN [32,48].…”

Section: Discussionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be upregulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly (ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

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Section: Discussionmentioning

confidence: 99%

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

et al. 2007

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“…(1)(2)(3). In addition, it is well known that mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of PD (4 -7).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Devi

Raghavendran

Prabhu

et al. 2008

Journal of Biological Chemistry

972

926

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␣-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human ␣-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of ␣-synuclein. Mitochondrial imported ␣-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type ␣-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial ␣-synuclein with A53T mutation as compared with wild-type ␣-synuclein. Importantly, ␣-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ϳ14-kDa ␣-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of ␣-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and ␣-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of ␣-synuclein with complex I. These results provide evidence that mitochondrial accumulated ␣-synuclein may interact with complex I and interfere with its functions. Parkinson disease (PD)2 is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta.

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“…The effects of phosphorylation of Ser-129 on ␣-SYNЈs conformation are not known, but phosphorylation at Ser-129 caused a 4-fold increase in insoluble ␣-SYN (114) and inhibited interaction of ␣-SYN with phospholipids and phospholipase D2 (116). G protein-coupled receptor kinases phosphorylate ␣-SYN at this single residue (116,117), and casein kinase 1 and 2 have been suggested as a responsible kinase (118). Chen and Feany (119) created a series of transgenic Drosophila to explore the role of phosphoserine 129 ␣-SYN in neurotoxicity to DA neurons.…”

Section: Concentrationmentioning

confidence: 99%

Lewy bodies

Shults

2006

Proc. Natl. Acad. Sci. U.S.A.

408

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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The role of α-synuclein in neurodegenerative diseases

Cited by 194 publications

References 206 publications

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

Lewy bodies

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