Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

Decressac, Mickaël; Mattsson, Bengt; Lundblad, Martin; Weikop, Pia; Björklund, Anders

doi:10.1016/j.nbd.2011.12.013

Cited by 230 publications

(278 citation statements)

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“…Lentiviral vectors expressing human wild type or mutant forms of α-synuclein have been shown to lead to a progressive loss of nigral dopaminergic neurons by 24-35% in rats over 5 months 37 whereas adenoviruses expressing human α-synuclein have been shown to decrease nigral dopaminergic neurons by up to 80% in as short as 6 weeks, however these results are less consistent. 11,12,[38][39][40][41] In our model, miR-7T-AsRed significantly reduced TH expression by one-third at week 16 and two thirds at week 24. However, staining with VMAT2, another neuronal marker showed that there was only a 30% loss of neurons at 24 weeks suggesting that the nigral neurons had downregulated their activity.…”

Section: Discussionmentioning

confidence: 55%

“…4,5,[11][12][13][14] However, there has been much controversy about the form of α-synuclein that could be toxic to neurons. Oligomers of α-synuclein as well as truncations and posttranslational modifications have been shown to play an important role in neuronal toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…10 Furthermore, overexpression of α-synuclein has been found to be toxic to dopaminergic neurons, implicating α-synuclein as a key player in the molecular mechanisms of the disease. [11][12][13][14] The mechanisms underlying α-synuclein toxicity are unclear but one hypothesis is that α-synuclein may be acting in the manner of a prion: transferring from cell-to-cell, thus spreading pathology. Braak and colleagues were the first to suggest that α-synuclein might be spreading throughout the brain with Lewy pathology first appearing in the dorsal motor nucleus of the vagal nerve and the olfactory bulb.…”

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

et al. 2017

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms show that miR-7 is decreased in the substantia nigra of patients with PD and therefore may play an essential role in the regulation of α-synuclein expression. Furthermore, we have found that lentiviral mediated expression of miR-7 complementary binding sites to stably induce a loss of miR-7 function results in an increase in α-synuclein expression in vitro and in vivo. We have also shown that depletion of miR-7 using a miR-decoy produces a loss of nigral dopaminergic neurons accompanied by a reduction of striatal dopamine content. These data suggest that miR-7 has an important role in the regulation of α-synuclein and dopamine physiology and may provide a new paradigm to study the pathology of PD.3

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

et al. 2017

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“…Changes in striatal DA release were studied at five different time points after vector injection that match progressively more advanced stages of α-synuclein-induced pathology: at 10 d and 3 wk after vector injection, when α-synuclein is fully expressed but before any major cell loss has occurred; at 5 wk, when DA neurodegeneration is well under way; and at 8 and 16 wk, when DA neuron cell loss is complete and the remaining neurons survive long-term in a compromised state, characterized by high levels α-synuclein expression and abundant signs of axonal pathology and loss of terminals (18). Recordings were made bilaterally in urethane-anesthetized rats from electrodes implanted into the center of the caudate putamen (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…AAV-mediated overexpression of α-synuclein provides an interesting model of PD-like pathology in that the degenerative changes develop progressively over time, from the early signs of axonal damage and α-synuclein aggregation, seen at 2-3 wk after vector injection, followed by neurodegeneration and DA neuron cell loss which develops over the subsequent weeks (14)(15)(16)(17)(18). This model offers an opportunity to monitor the functional changes that take place in α-synuclein-overexpressing DA neurons at stages that match the presymptomatic, early, and advanced stages of the human disease.…”

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Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Lundblad

Decressac

Mattsson

et al. 2012

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

252

221

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We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)-α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70-80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8-16 wk, overall striatal innervation density was reduced by 60-80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80-90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and earlystage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.neurodegeneration | synaptic transmission I n Parkinson disease (PD) damage to axons and axonal terminals is likely to precede any overt dopamine (DA) neuron cell death, suggesting that the disease process may start at the axon terminal level and progress retrogradely to affect the cell bodies. Support of this idea comes from autopsy studies of brains from PD patients, which suggest that the extent of damage to the DA terminals in caudate nucleus and putamen at the time of disease onset is more extensive than the loss of DA neurons in the substantia nigra (see ref. 1 for a recent review). Although genuine longitudinal data are difficult to obtain in human material, available postmortem data indicate that the loss of DA in the caudate nucleus at the time of onset of symptoms is on the order of 70-80%, whereas as much as 70% of the nigral DA cell bodies may still be alive (1-5). Measurement of binding to the vesicular monoamine transporter (VMAT), which is likely to be a good measure of the functional integrity of the DA terminals, has shown severe loss of VMAT in the caudate nucleus early in the disease in some patients (6).Together, these data suggest that impairments at the terminal/ synaptic level may be a prominent feature of presymptomatic and early-stage PD and that impaired DA neurotransmission may contribute to the functional deficits seen also at more advanced stages of the disea...

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Do subjects with minimal motor features have prodromal Parkinson disease?

Chu

Buchman

Olanow³

et al. 2018

Annals of Neurology

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Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

Cited by 230 publications

References 41 publications

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Do subjects with minimal motor features have prodromal Parkinson disease?

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