| 1. |
- Decressac, Mickael, et al.
(författare)
-
Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson's disease
- 2012
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 235:1, s. 306-315
-
Tidskriftsartikel (refereegranskat)abstract
- Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein alpha-synuclein (alpha-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-alpha-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-alpha-syn models. However, alpha-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the alpha-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-alpha-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-alpha-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models. (C) 2012 Elsevier Inc. All rights reserved.
|
|
| 2. |
- Decressac, Mickael, et al.
(författare)
-
GDNF fails to exert neuroprotection in a rat {alpha}-synuclein model of Parkinson's disease.
- 2011
-
Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 134:8, s. 2302-2311
-
Tidskriftsartikel (refereegranskat)abstract
- The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by α-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before α-synuclein, was inefficient in preventing the wild-type α-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal α-synuclein-positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on α-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type α-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease.
|
|
| 3. |
|
|
| 4. |
- Decressac, Mickael, et al.
(författare)
-
mTOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats
- 2013
-
Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 3:1, s. 13-17
-
Tidskriftsartikel (refereegranskat)abstract
- The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients.
|
|
| 5. |
- Decressac, Mickael, et al.
(författare)
-
Neuropeptide Y and its role in CNS disease and repair.
- 2012
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 238:2, s. 265-272
-
Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) is widely expressed throughout the CNS and exerts a number of important physiological functions as well as playing a role in pathological conditions such as obesity, anxiety, epilepsy, chronic pain and neurodegenerative disorders. In this review, we highlight some of the recent advances in our understanding of NPY biology and how this may help explain not only its role in health and disease, but also its possible use therapeutically.
|
|
| 6. |
- Decressac, Mickael, et al.
(författare)
-
NURR1 in Parkinson disease-from pathogenesis to therapeutic potential.
- 2013
-
Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 9:11, s. 629-636
-
Forskningsöversikt (refereegranskat)abstract
- In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathology affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clinical and experimental data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.
|
|
| 7. |
- Decressac, Mickael, et al.
(författare)
-
Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.
- 2012
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 45:3, s. 939-953
-
Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.
|
|
| 8. |
- Decressac, Mickael, et al.
(författare)
-
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:19, s. 1817-1826
-
Tidskriftsartikel (refereegranskat)abstract
- The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.
|
|
| 9. |
- Decressac, Mickael, et al.
(författare)
-
TFEB: Pathogenic role and therapeutic target in Parkinson disease.
- 2013
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 9:8, s. 1244-1246
-
Tidskriftsartikel (refereegranskat)abstract
- Parkinson disease (PD) is characterized by the progressive loss of nigral dopamine neurons and the presence of accumulations containing the disease-causing protein SNCA/α-synuclein. Here we review our recent findings describing how SNCA impairs the function of the master regulator of the autophagy-lysosomal pathway (ALP), the transcription factor EB (TFEB), and that genetic or pharmacological stimulation of its activity promotes protection of dopamine neurons. These findings suggest that strategies aimed at enhancing autophagy-mediated degradation of SNCA may hold great promise for disease intervention in PD.
|
|
| 10. |
- Decressac, Mickael, et al.
(författare)
-
α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons.
- 2012
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 4:163, s. 156-163
-
Tidskriftsartikel (refereegranskat)abstract
- Glial cell line-derived neurotrophic factor (GDNF) and its close relative neurturin are currently in clinical trials for neuroprotection in patients with Parkinson disease (PD). However, in animal models of PD, GDNF fails to protect nigral dopamine (DA) neurons against α-synuclein-induced neurodegeneration. Using viral vector delivery of human wild-type α-synuclein to nigral DA neurons in rats, we show that the intracellular response to GDNF is blocked in DA neurons that overexpress α-synuclein. This block is accompanied by reduced expression of the transcription factor Nurr1 and its downstream target, the GDNF receptor Ret. We found that Ret expression was also reduced in nigral DA neurons in PD patients. Conditional knockout of Nurr1 in mice resulted in reduced Ret expression and blockade of the response to GDNF, whereas overexpression of Nurr1 restored signaling, providing protection of nigral DA neurons against α-synuclein toxicity. These results suggest that Nurr1 is a regulator of neurotrophic factor signaling and a key player in the cellular defense against α-synuclein toxicity.
|
|
| 11. |
- Kadkhodaei, Banafsheh, et al.
(författare)
-
Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:6, s. 2360-2365
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease.
|
|
| 12. |
- Lundblad, Martin, et al.
(författare)
-
Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons.
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 109:9, s. 3213-3219
-
Tidskriftsartikel (refereegranskat)abstract
- 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 early-stage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.
|
|
| 13. |
- Tamburrino, Anna, et al.
(författare)
-
Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson's disease.
- 2015
-
Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 3:1
-
Tidskriftsartikel (refereegranskat)abstract
- The early clinical trials using fetal ventral mesencephalic (VM) allografts in Parkinson's disease (PD) patients have shown efficacy (albeit not in all cases) and have paved the way for further development of cell replacement therapy strategies in PD. The preclinical work that led to these clinical trials used allografts of fetal VM tissue placed into 6-OHDA lesioned rats, while the patients received similar allografts under cover of immunosuppression in an α-synuclein disease state. Thus developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic.
|
|
| 14. |
|
|
| 15. |
- Ulusoy, Ayse, et al.
(författare)
-
Viral vector-mediated overexpression of α-synuclein as a progressive model of Parkinson's disease
- 2010
-
Ingår i: Progress in Brain Research. - 1875-7855. ; 184, s. 89-111
-
Forskningsöversikt (refereegranskat)abstract
- The discovery of the role of α-synuclein in the pathogenesis of Parkinson's disease (PD) has opened new possibilities for the development of more authentic models of Parkinson's disease. Recombinant adeno-associated virus (AAV) and lentivirus (LV) vectors are efficient tools for expression of genes locally in subsets of neurons in the brain and can be used to express human wild-type or mutated α-synuclein selectively in midbrain dopamine neurons. Using this approach, it is possible to trigger extensive PD-like cellular and axonal pathologies in the nigrostriatal projection, involving abnormal protein aggregation, neuronal dysfunction, and cell death that develop progressively over time. Targeted overexpression of human α-synuclein in midbrain dopamine neurons, using AAV vectors, reproduces many of the characteristic features of the human disease and provides, for the first time, a model of progressive PD that can be applied to both rodents and primates.
|
|
| 16. |
- Volakakis, Nikolaos, et al.
(författare)
-
Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression
- 2015
-
Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 35:42, s. 14370-14385
-
Tidskriftsartikel (refereegranskat)abstract
- α-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease.
|
|
