Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease

Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.     

Lack of reduction in body fat after treatment with insulin-like growth factor-I in two children with growth hormone gene deletions

Two patients with growth hormone (GH) gene deletions were treated with recombinant insulin-like growth factor-I (IGF-I) (80-240 (microg/kg/day) and the effects on bone mass and body composition were compared to administration of GH (0.075 U/kg/day) to 8 patients with idiopathic GH deficiency. Bone mass and body composition were measured by dual photon X-ray absorptiometry (DEXA ) before and 3 and 6 months after treatment with GH or IGF-I. Similar increases in growth velocities were observed after GH and IGF-I treatment. Treatment with GH resulted in prompt and significant reduction in body fat percentage (basal, 3 and 6 months: 22+/-10, 17+/-9, and 16+/-9%) whereas body fat percentage remained unchanged after IGF-I therapy (basal, 3 and 6 months: 49, 52 and 48% in patient 1 and 45, 42 and 43% in patient 2, respectively). Fat percentage remained elevated after 18 months of IGF-I treatment in patients 1 (51%) and 2 (44%), respectively. Lean mass and bone mineral content increased with GH and IGF-I therapies. We conclude that reduction of body fat measured by DEXA, observed after administration of GH but not after IGF-I treatment in these children with GH deficiency, suggests that the GH effect on body fat mass is not mediated by circulating IGF-I.