Limits...
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.

Show MeSH

Related in: MedlinePlus

Progression of the neurodegenerative phenotype is delayed by Parkin deficiency in hA30Pα-syn mice.(A) Motor function was assessed by evaluating the hindlimb extension reflex (upper graph) and rotarod performance (lower graph). Mean performance is plotted against age for each genotype and the curvature and slope of parabolic regressions were analysed statistically (n = 10–16). #, slope and curvature different from wild-type and parkin −/− with p<0.0001; *, different curvatures with p<0.05. (B) Age-dependent penetrance of the neurodegenerative phenotype in hA30Pα-syn mice with or without Parkin (n = 12–14). *, p<0.01 (Kaplan-Meier analysis).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2722082&req=5

pone-0006629-g002: Progression of the neurodegenerative phenotype is delayed by Parkin deficiency in hA30Pα-syn mice.(A) Motor function was assessed by evaluating the hindlimb extension reflex (upper graph) and rotarod performance (lower graph). Mean performance is plotted against age for each genotype and the curvature and slope of parabolic regressions were analysed statistically (n = 10–16). #, slope and curvature different from wild-type and parkin −/− with p<0.0001; *, different curvatures with p<0.05. (B) Age-dependent penetrance of the neurodegenerative phenotype in hA30Pα-syn mice with or without Parkin (n = 12–14). *, p<0.01 (Kaplan-Meier analysis).

Mentions: As expected, adult transgenic hA30Pα-syn mice with or without Parkin developed a neurodegenerative phenotype with age-dependent penetrance, characterized by rapidly deteriorating motor performance, resulting in paralysis of the hindlimbs within approximately one month of the appearance of the first observable clinical signs (unsteady gait, hindlimb weakness and dragging) [14]. These symptoms developed in the absence of degeneration of the nigral dopaminergic neurons [14] (Results S1, Figure S2 and Table S1), a neuronal population in which human α-synuclein was not detected by immunohistochemistry (Results S1, Figure S1B). We investigated whether Parkin deficiency affected the incidence and the progression of this neurodegenerative phenotype: hA30Pα-syn mice with or without a functional parkin gene and their littermates of wild-type and parental genotypes were followed from 9 months of age until death to unravel potential disease-predictive changes in motor function (Figure 2). Every week, we tested the hindlimb extension reflex, which is altered by motor neuron diseases [38], and performance on a rotarod, which is progressively impaired in hA30Pα-syn mice [39]. The mean performance in each task was plotted against age for each genotype and the trends were analysed using a second order polynomial curve fit (Figure 2A). The mean performance of wild-type and parkin −/− mice in both tasks was similar and remained constant throughout the testing period; in contrast, a progressive, disease-predictive decline in performance was observed in hA30Pα-syn mice. In addition, the decline in performance of both tasks was significantly delayed in the absence of Parkin (Figure 2A).


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)

Progression of the neurodegenerative phenotype is delayed by Parkin deficiency in hA30Pα-syn mice.(A) Motor function was assessed by evaluating the hindlimb extension reflex (upper graph) and rotarod performance (lower graph). Mean performance is plotted against age for each genotype and the curvature and slope of parabolic regressions were analysed statistically (n = 10–16). #, slope and curvature different from wild-type and parkin −/− with p<0.0001; *, different curvatures with p<0.05. (B) Age-dependent penetrance of the neurodegenerative phenotype in hA30Pα-syn mice with or without Parkin (n = 12–14). *, p<0.01 (Kaplan-Meier analysis).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006629-g002: Progression of the neurodegenerative phenotype is delayed by Parkin deficiency in hA30Pα-syn mice.(A) Motor function was assessed by evaluating the hindlimb extension reflex (upper graph) and rotarod performance (lower graph). Mean performance is plotted against age for each genotype and the curvature and slope of parabolic regressions were analysed statistically (n = 10–16). #, slope and curvature different from wild-type and parkin −/− with p<0.0001; *, different curvatures with p<0.05. (B) Age-dependent penetrance of the neurodegenerative phenotype in hA30Pα-syn mice with or without Parkin (n = 12–14). *, p<0.01 (Kaplan-Meier analysis).
Mentions: As expected, adult transgenic hA30Pα-syn mice with or without Parkin developed a neurodegenerative phenotype with age-dependent penetrance, characterized by rapidly deteriorating motor performance, resulting in paralysis of the hindlimbs within approximately one month of the appearance of the first observable clinical signs (unsteady gait, hindlimb weakness and dragging) [14]. These symptoms developed in the absence of degeneration of the nigral dopaminergic neurons [14] (Results S1, Figure S2 and Table S1), a neuronal population in which human α-synuclein was not detected by immunohistochemistry (Results S1, Figure S1B). We investigated whether Parkin deficiency affected the incidence and the progression of this neurodegenerative phenotype: hA30Pα-syn mice with or without a functional parkin gene and their littermates of wild-type and parental genotypes were followed from 9 months of age until death to unravel potential disease-predictive changes in motor function (Figure 2). Every week, we tested the hindlimb extension reflex, which is altered by motor neuron diseases [38], and performance on a rotarod, which is progressively impaired in hA30Pα-syn mice [39]. The mean performance in each task was plotted against age for each genotype and the trends were analysed using a second order polynomial curve fit (Figure 2A). The mean performance of wild-type and parkin −/− mice in both tasks was similar and remained constant throughout the testing period; in contrast, a progressive, disease-predictive decline in performance was observed in hA30Pα-syn mice. In addition, the decline in performance of both tasks was significantly delayed in the absence of Parkin (Figure 2A).

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