?-Synuclein expression in substantia nigra and cortex in Parkinson's disease

Neystat, Michael; Lynch, Timothy; Przedborski, Serge; Kholodilov, Nikolai; Rzhetskaya, Margarita; Burke, Robert E.

doi:10.1002/1531-8257(199905)14:3<417::aid-mds1005>3.0.co;2-x

Cited by 96 publications

(73 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, levels of ␣-synuclein depend on its phosphorylation and ubiquitination, which influence its degradation rate (Vekrellis et al, 2004). Interestingly, disparities between ␣-synuclein mRNA and protein levels were reported previously during brain development and in neurodegenerative disorders associated with accumulation of ␣-synuclein, in which the protein levels increased, whereas its mRNA content remained decreased or unchanged (Neystat et al, 1999;Petersen et al, 1999;Ozawa et at., 2001).…”

Section: Discussionmentioning

confidence: 86%

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

Ziółkowska

Gieryk²,

Bilecki³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

Chronic exposure to opiates produces dependence and addiction, which may result from neuroadaptations in the dopaminergic reward pathway and its target brain regions. The neuronal protein ␣-synuclein has been implicated in neuronal plasticity and proposed to serve as a negative regulator of dopamine neurotransmission. Thus, ␣-synuclein could mediate some effects of opiates in the brain. The present study investigated the influence of acute and chronic morphine administration on ␣-synuclein mRNA and protein expression in the brains of mice. Downregulation of ␣-synuclein mRNA was observed in the basolateral amygdala, dorsal striatum, nucleus accumbens, and ventral tegmental area of mice withdrawn from chronic morphine treatment. The changes were the most pronounced after longer periods of withdrawal (48 h). In contrast, levels of ␣-synuclein protein, as assessed by Western blotting, were significantly increased in the amygdala and striatum/accumbens (but not in the mesencephalon) of morphine-withdrawn mice. In both brain regions, levels of ␣-synuclein were elevated for as long as 2 weeks after treatment cessation. Because ␣-synuclein is a presynaptic protein, the detected opposite changes in its mRNA and protein levels are likely to take place in different populations of projection neurons whose somata are in different brain areas. Axonal localization of ␣-synuclein was confirmed by immunofluorescent labeling. An attempt to identify postsynaptic neurons innervated by ␣-synuclein-containing axon terminals revealed their selective apposition to calbindin D28K-negative projection neurons in the basolateral amygdala. The observed changes in ␣-synuclein levels are discussed in connection with their putative role in mediating suppression of dopaminergic neurotransmission during opiate withdrawal.

show abstract

Section: Discussionmentioning

confidence: 86%

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

Ziółkowska

Gieryk²,

Bilecki³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…SNCA transcription is significantly reduced (see Table 2) in the parkinsonian SN [32,48]. Here, we describe gene regulatory relationships between SNCA and two other pathways considered to be of relevance in PD, dopamine synthesis and parkin metabolism.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

“…However, longitudinal follow-up of an asymptomatic mutation carrier who still expresses the mutated allele will be necessary to demonstrate whether decreased expression of the mutant mRNA precedes disease onset. The notion of haploinsufficiency was also evoked in a second study showing reduced h-synuclein expression in the substantia nigra of nine histologically proven PD patients without known h-synuclein mutations [73]. Aggregation of h-synuclein might also cause h-synuclein deficiency by entrapping the protein, thus reducing the amount of available functional h-synuclein ( fig.…”

Section: Factors Acceleratingmentioning

confidence: 99%

“…Subsequently, however, searches for these two mutations in the h-synuclein gene in many familial (dominant and recessive), sporadic, and early-onset PD patients have proven unsuccessful [62][63][64][65][66][67][68][69]. Other mutations in the h-synuclein gene have also been sought: the entire coding region of h-synuclein (using as templates either cDNA or genomic DNA including exon/ intron boundaries) was sequenced in 61 autosomal dominant PD families [64,70,71], in 21 PD patients with at least one affected first-degree relative [72,73], in 7 isolated PD cases [73], and in 24 pathologically proven sporadic PD cases [74]. Very recently, 28 autosomal dominant PD families and 158 cases with at least one affected relative were screened by singlestrand conformational polymorphism (SSCP) [75].…”

Section: Geneticsmentioning

confidence: 99%

Alpha-synuclein and Parkinson's disease

Lücking¹,

Brice²

2000

CMLS, Cell. Mol. Life Sci.

262

215

View full text Add to dashboard Cite

The involvement of alpha-synuclein in neurodegenerative diseases was first suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD). Later, two different alpha-synuclein mutations were shown to be associated with autosomal-dominant Parkinson's disease (PD), but only in a small number of families. However, the discovery that alpha-synuclein is a major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD, confirmed its role in PD pathogenesis. Pathological aggregation of the protein might be responsible for neurodegeneration. In addition, soluble oligomers of alpha-synuclein might be even more toxic than the insoluble fibrils found in Lewy bodies. Multiple factors have been shown to accelerate alpha-synuclein aggregation in vitro. Therapeutic strategies aimed to prevent this aggregation are therefore envisaged. Although little has been learned about its normal function, alpha-synuclein appears to interact with a variety of proteins and membrane phospholipids, and may therefore participate in a number of signaling pathways. In particular, it may play a role in regulating cell differentiation, synaptic plasticity, cell survival, and dopaminergic neurotransmission. Thus, pathological mechanisms based on disrupted normal function are also possible.

show abstract

?-Synuclein expression in substantia nigra and cortex in Parkinson's disease

Cited by 96 publications

References 18 publications

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

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

Alpha-synuclein and Parkinson's disease

Contact Info

Product

Resources

About