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Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.

Fournier M, Vitte J, Garrigue J, Langui D, Dullin JP, Saurini F, Hanoun N, Perez-Diaz F, Cornilleau F, Joubert C, Ardila-Osorio H, Traver S, Duchateau R, Goujet-Zalc C, Paleologou K, Lashuel HA, Haass C, Duyckaerts C, Cohen-Salmon C, Kahle PJ, Hamon M, Brice A, Corti O - PLoS ONE (2009)

Bottom Line: The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons.As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein.However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy.

View Article: PubMed Central - PubMed

Affiliation: Université Pierre et Marie Curie-Paris 6, CRICM (Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière), UMR-S975, Paris, France.

ABSTRACT
In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

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PS129-α-synuclein-immunoreactivity is associated with activation of caspase 9.(A) Examples of PS129-α-synuclein-positive neurons with abnormally shaped nuclei and dysmorphic or abnormally swollen somata and proximal dendrites in the brainstem of symptomatic hA30Pα-syn mice. The upper and lower right micrographs correspond to a higher magnification of the regions outlined by the frames in the left micrograph. (B) Double immunofluorescent labelling showing caspase 9 activation in representative PS129-α-synuclein- or ubiquitin-positive neurons of the spinal cord. Scale bars indicate 30 µm in (A) and 15 µm in (B).
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pone-0006629-g008: PS129-α-synuclein-immunoreactivity is associated with activation of caspase 9.(A) Examples of PS129-α-synuclein-positive neurons with abnormally shaped nuclei and dysmorphic or abnormally swollen somata and proximal dendrites in the brainstem of symptomatic hA30Pα-syn mice. The upper and lower right micrographs correspond to a higher magnification of the regions outlined by the frames in the left micrograph. (B) Double immunofluorescent labelling showing caspase 9 activation in representative PS129-α-synuclein- or ubiquitin-positive neurons of the spinal cord. Scale bars indicate 30 µm in (A) and 15 µm in (B).

Mentions: Whether there is a causative relationship between PS129-α-synuclein accumulation and the pathogenesis of synucleinopathies is currently a matter of debate [40], [41]–[44]. In diseased hA30Pα-syn mice, many PS129-α-synuclein-positive neuronal cell bodies were abnormally shaped, with dysmorphic nuclei or aberrantly swollen cytoplasm and proximal neurites, whether or not they accumulated ubiquitin (Figure 8A). Cleaved capase 9 immunoreactivity has been reported in viral vector-based models of synucleinopathy [44], [45], so we evaluated activation of caspase 9 in end-stage hA30Pα-syn mice (Figure 8B). Cleaved caspase 9 was found in approximately 5% of the neuronal cell bodies accumulating PS129-α-synuclein in the spinal cords of transgenic mice (7.4±1.8% with and 4.5%±2.2 without Parkin; p = 0.4), and in a similar proportion of cell bodies of neurons accumulating both PS129-α-synuclein and ubiquitin (6.3%±2.8 in the presence of Parkin, 6.7%±2.9 in its absence; p = 0.9). Importantly, deposits of PS129-α-synuclein were present in more than 90% of the neurons in which caspase 9 was activated in hA30Pα-syn mice both with (92.0%±3.2) and without Parkin (96.0%±3.1; p = 0. 4).


Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.

Fournier M, Vitte J, Garrigue J, Langui D, Dullin JP, Saurini F, Hanoun N, Perez-Diaz F, Cornilleau F, Joubert C, Ardila-Osorio H, Traver S, Duchateau R, Goujet-Zalc C, Paleologou K, Lashuel HA, Haass C, Duyckaerts C, Cohen-Salmon C, Kahle PJ, Hamon M, Brice A, Corti O - PLoS ONE (2009)

PS129-α-synuclein-immunoreactivity is associated with activation of caspase 9.(A) Examples of PS129-α-synuclein-positive neurons with abnormally shaped nuclei and dysmorphic or abnormally swollen somata and proximal dendrites in the brainstem of symptomatic hA30Pα-syn mice. The upper and lower right micrographs correspond to a higher magnification of the regions outlined by the frames in the left micrograph. (B) Double immunofluorescent labelling showing caspase 9 activation in representative PS129-α-synuclein- or ubiquitin-positive neurons of the spinal cord. Scale bars indicate 30 µm in (A) and 15 µm in (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2722082&req=5

pone-0006629-g008: PS129-α-synuclein-immunoreactivity is associated with activation of caspase 9.(A) Examples of PS129-α-synuclein-positive neurons with abnormally shaped nuclei and dysmorphic or abnormally swollen somata and proximal dendrites in the brainstem of symptomatic hA30Pα-syn mice. The upper and lower right micrographs correspond to a higher magnification of the regions outlined by the frames in the left micrograph. (B) Double immunofluorescent labelling showing caspase 9 activation in representative PS129-α-synuclein- or ubiquitin-positive neurons of the spinal cord. Scale bars indicate 30 µm in (A) and 15 µm in (B).
Mentions: Whether there is a causative relationship between PS129-α-synuclein accumulation and the pathogenesis of synucleinopathies is currently a matter of debate [40], [41]–[44]. In diseased hA30Pα-syn mice, many PS129-α-synuclein-positive neuronal cell bodies were abnormally shaped, with dysmorphic nuclei or aberrantly swollen cytoplasm and proximal neurites, whether or not they accumulated ubiquitin (Figure 8A). Cleaved capase 9 immunoreactivity has been reported in viral vector-based models of synucleinopathy [44], [45], so we evaluated activation of caspase 9 in end-stage hA30Pα-syn mice (Figure 8B). Cleaved caspase 9 was found in approximately 5% of the neuronal cell bodies accumulating PS129-α-synuclein in the spinal cords of transgenic mice (7.4±1.8% with and 4.5%±2.2 without Parkin; p = 0.4), and in a similar proportion of cell bodies of neurons accumulating both PS129-α-synuclein and ubiquitin (6.3%±2.8 in the presence of Parkin, 6.7%±2.9 in its absence; p = 0.9). Importantly, deposits of PS129-α-synuclein were present in more than 90% of the neurons in which caspase 9 was activated in hA30Pα-syn mice both with (92.0%±3.2) and without Parkin (96.0%±3.1; p = 0. 4).

Bottom Line: The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons.As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein.However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy.

View Article: PubMed Central - PubMed

Affiliation: Université Pierre et Marie Curie-Paris 6, CRICM (Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière), UMR-S975, Paris, France.

ABSTRACT
In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

Show MeSH
Related in: MedlinePlus