Dopamine and α-synuclein dysfunction in Smad3 null mice

Departamento de Neurobiología-Investigación, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain.
Molecular Neurodegeneration (Impact Factor: 6.56). 10/2011; 6(1):72. DOI: 10.1186/1750-1326-6-72
Source: PubMed


Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-β1 (TGF-β1) levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade.
Striatal monoamine oxidase (MAO)-mediated dopamine (DA) catabolism to 3,4-dihydroxyphenylacetic acid (DOPAC) is strongly increased, promoting oxidative stress that is reflected by an increase in glutathione levels. Fewer astrocytes are detected in the ventral midbrain (VM) and striatal matrix, suggesting decreased trophic support to dopaminergic neurons. The SN of these mice has dopaminergic neuronal degeneration in its rostral portion, and the pro-survival Erk1/2 signalling is diminished in nigra dopaminergic neurons, not associated with alterations to p-JNK or p-p38. Furthermore, inclusions of α-synuclein are evident in selected brain areas, both in the perikaryon (SN and paralemniscal nucleus) or neurites (motor and cingulate cortices, striatum and spinal cord). Interestingly, these α-synuclein deposits are detected with ubiquitin and P(S129)-α-synuclein in a core/halo cellular distribution, which resemble those observed in human Lewy bodies (LB).
Smad3 deficiency promotes strong catabolism of DA in the striatum (ST), decrease trophic and astrocytic support to dopaminergic neurons and may induce α-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in α-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents.

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    • "The total number of BrdU-ir cells was estimated by multiplying the number of profiles by the sampling interval. For cell phenotyping, co-localization of Smad3 and BrdU with the different markers was assessed by confocal microscopy [22]. "
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    • "In addition, there is ample evidence that TGF-␤ promotes the survival of dopaminergic neurons in the substantia nigra [53]. A preliminary study in knockout mice showed that disruption of the TGF-␤ signalling cascade in neurons promotes catabolism of DA in the striatum, decreased trophic and astrocytic support to dopaminergic neurons, as well as possibly inducing ␣-synuclein accumulation [54]. Recently, a radiotracer named [ 89 Zr]-fresolimumab was preclinically evaluated in vitro and in vivo for the detection and quantification of tumours that overexpress TGF␤ [55]. "
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    • "Parkinson's disease (PD) is a symptoms such as resting tremor, muscle rigidity, bradykinesia and postural instability [1] [2] [3] [4]. Histopathological characteristics found inclusion bodies in substantia nigra component of Lewy bodies is α ITB J. Sci., Vol. "
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