Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra

Garcia-Reitboeck, Pablo; Anichtchik, Oleg; Dalley, Jeffrey W.; Ninkina, Natalia; Tofaris, George K.; Buchman, Vladimir L.; Spillantini, Maria Grazia

doi:10.1016/j.expneurol.2013.07.015

Cited by 65 publications

(67 citation statements)

References 32 publications

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“…Finally, in another study, surprisingly, the number of TH positive neurons is profoundly reduced in the SN of developing homozygous and heterozygous SNCA knockout embryos compared to WT embryos, suggesting that endogenous SNCA plays an important role in the embryonic development of DA neurons [71].…”

Section: Snca (Park1/park4)mentioning

confidence: 88%

“…As previously mentioned, Pitx3 is necessary for Nurr1-mediated transcription, an important mechanism in DA neuron development and maintenance. As such, Pitx3 mutations may increase susceptibility to PD by a downstream effect on Nurr1 activity and the subsequent reduction in the numbers of DA neurons formed in the SN during brain development, Endogenous a-synuclein has also been implicated in DA neuronal development [71]. In this study, Garcia-Reitboeck and colleagues describe a reduction in the number of DA neurons in the SN of mice with a spontaneous deletion of the SNCA gene, as well as in SNCA knockout (KO) mice, visible as early as E13.5.…”

Section: Evidence For a Developmental Component Of Pd: Deregulated Emmentioning

confidence: 99%

“…Recently, these mice were used to generate a new transgenic line by crossing them with WT mice. Compared to WT or to the 1-120 SNCA transgenic line, a significant increase in the number of SN DA neurons was observed [71]. The group, however, did not investigate the correlation between the increase of TH-positive neurons with increased neurogenesis nor did they investigate the proliferation, differentiation or survival potential of these cells, which would be an interesting point for future research.…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

See 2 more Smart Citations

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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Section: Snca (Park1/park4)mentioning

confidence: 88%

Section: Evidence For a Developmental Component Of Pd: Deregulated Emmentioning

confidence: 99%

Section: Snca (Park1/park4)mentioning

confidence: 99%

See 1 more Smart Citation

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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“…In the striatum of these mice alpha-synuclein accumulation is associated with SNARE complex protein redistribution and deficit in dopamine release (Garcia-Reitböck et al, 2010). Using this model we have also identified a role for alpha-synuclein in dopaminergic cell development (Garcia-Reitboeck et al, 2013).…”

Section: Animal Models Of Alpha-synuclein Pathology And/or Spreadingmentioning

confidence: 95%

Parkinson's disease as a member of Prion-like disorders

Herva

Spillantini

2015

Virus Research

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“…For instance, α-syn acts as a negative regulator of nigrostriatal dopaminergic neuron function (Abeliovich et al, 2000;Larsen et al, 2006). Studies on α-syn-null mice that carry a spontaneous deletion of the gene locus encoding α-syn (C57BL/ 6JOlaHsd mice; Specht and Schoepfer, 2001) and resemble α-synspecific knockout mice in terms of dopamine release, dopamine transporter (DAT, also known as SLC6A3) expression, striatal dopamine reuptake and nigral dopamine neuron number (Garcia-Reitboeck et al, 2013) have shown that α-syn decreases the refilling rate of readily releasable dopamine pools (Yavich et al, 2004). The decrease of dopamine overflow in these mice is not dependent on dopamine D2 autoreceptors misfunctioning or changes in dopamine re-uptake , thus indicating that other molecules, affected by the absence of α-syn, contribute to this phenomenon.…”

Section: Introductionmentioning

confidence: 99%

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

Zaltieri

Grigoletto

Longhena

et al. 2015

Journal of Cell Science

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104

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The main neuropathological features of Parkinson's disease are dopaminergic nigrostriatal neuron degeneration, and intraneuronal and intraneuritic proteinaceous inclusions named Lewy bodies and Lewy neurites, respectively, which mainly contain α-synuclein (α-syn, also known as SNCA). The neuronal phosphoprotein synapsin III (also known as SYN3), is a pivotal regulator of dopamine neuron synaptic function. Here, we show that α-syn interacts with and modulates synapsin III. The absence of α-syn causes a selective increase and redistribution of synapsin III, and changes the organization of synaptic vesicle pools in dopamine neurons. In α-syn-null mice, the alterations of synapsin III induce an increased locomotor response to the stimulation of synapsin-dependent dopamine overflow, despite this, these mice show decreased basal and depolarization-dependent striatal dopamine release. Of note, synapsin III seems to be involved in α-syn aggregation, which also coaxes its increase and redistribution. Furthermore, synapsin III accumulates in the caudate and putamen of individuals with Parkinson's disease. These findings support a reciprocal modulatory interaction of α-syn and synapsin III in the regulation of dopamine neuron synaptic function.

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Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra

Cited by 65 publications

References 32 publications

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Parkinson's disease as a member of Prion-like disorders

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

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