Dataset Information

Dopamine and ?-synuclein dysfunction in Smad3 null mice.

ABSTRACT:

Background

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-?1 (TGF-?1) 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-?1 signalling cascade.

Results

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 ?-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 ?-synuclein deposits are detected with ubiquitin and P(S129)-?-synuclein in a core/halo cellular distribution, which resemble those observed in human Lewy bodies (LB).

Conclusions

Smad3 deficiency promotes strong catabolism of DA in the striatum (ST), decrease trophic and astrocytic support to dopaminergic neurons and may induce ?-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in ?-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents.

SUBMITTER: Tapia-Gonzalez S

PROVIDER: S-EPMC3219599 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Publications

Dopamine and α-synuclein dysfunction in Smad3 null mice.

Tapia-González Silvia S Giráldez-Pérez Rosa M RM Cuartero M Isabel MI Casarejos M José MJ Mena M Ángeles MÁ Wang Xiao-Fan XF Sánchez-Capelo Amelia A

Molecular neurodegeneration 20111013

<h4>Background</h4>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.<h4>Results</h4>Striatal monoamine oxidase (MAO)-mediated dopamine (DA) catabolism to 3,4-dihydroxyphe ...[more]

PMID: 21995845

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