transforming-growth-factor-alpha and Parkinsonian-Disorders

We examined the cell proliferative, neurogenic, and behavioral effects of transforming growth factor alpha (TGFalpha) in a 6-OHDA Parkinson's disease model when compared with naive rats. Intrastriatal TGFalpha infusion induced significant proliferation, hyperplastic nodules, and substantial migratory waves of nestin-positive progenitor cells from the adult subventricular zone (SVZ) of dopamine-denervated rats. Interestingly, SVZ cells in naive rats displayed proliferation but minimal migration in response to the TGFalpha infusion. The cells in the expanded SVZ accumulated cytoplasmic beta-catenin, indicating activation of classical Wnt signaling. However, no evidence of any neuronal differentiation was found of these recruited progenitor cells anywhere examined in the brain. Consequently, no evidence of dopaminergic (DA) neurogenesis was found in the striatum or substantia nigra in any experimental group, and amphetamine-induced behavioral rotations did not improve. In summary, the cells in the TGFalpha-induced migratory cellular wave remain undifferentiated and do not differentiate into midbrain-like DA neurons.

Topics: Animals; Behavior, Animal; beta Catenin; Bromodeoxyuridine; Cell Movement; Cell Proliferation; Corpus Striatum; Cytoskeletal Proteins; Disease Models, Animal; Dopamine; Drug Administration Routes; Intermediate Filament Proteins; Lateral Ventricles; Male; Nerve Tissue Proteins; Nestin; Neurons; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Stem Cells; Trans-Activators; Transforming Growth Factor alpha; Tyrosine 3-Monooxygenase

A susceptibility gene for Parkinson's disease (PD) with late onset and typical Lewy-body pathology maps to chromosome 2p13 (PARK3). In the present study we examined the gene for transforming growth factor alpha (TGF alpha), which is located in the PARK3-region, as a potential candidate gene. This polypeptide mitogen exerts trophic actions on dopaminergic neurons and TGF alpha-deficient mice have fewer dopaminergic neurons. We did not find mutations in the exonic or exon-flanking intronic sequences of index patients of two families linked to 2p13. This result excludes mutations in the coding region of TGF alpha as a cause for hereditary PD, but does not rule out a possible role of sequence variants in regulatory regions or splice sites.

Topics: Base Sequence; Chromosomes, Human, Pair 2; DNA Mutational Analysis; Dopamine; Exons; Female; Genetic Testing; Humans; Introns; Male; Mutation; Parkinsonian Disorders; Substantia Nigra; Transforming Growth Factor alpha