Until recently, glial-derived neurotrophic factor (GDNF) had been the superstar in the arena of protecting substantia nigra cells in Parkinson disease. Research in several animal models had confirmed that GDNF protects both substantia nigra neurons and their axons in the striatum, and an open-label trial of the neurotrophin delivered directly into the striatum (specifically, the putamen) showed promising results (see ARF related news story). However, this summer, a similar double-blind, placebo controlled trial of GDNF delivery failed to meet its endpoints after six months (see Amgen press release).

While the attention was on GDNF, Pedro Lowenstein and Maria Castro of the Cedars Sinai Medical Center and the University of California, Los Angeles, set their sights on the morphogenetic Shh pathway because it is critical for the proper development of dopaminergic neurons. Previous research has found that Shh injected directly into the striatum—the terminal area for substantia nigra dopaminergic neurons—can prevent some nigrostriatal neurons from dying (Tsuboi and Shults, 2002). In the present study, first author Andres Hurtado-Lorenzo and colleagues used an adenoviral vector to deliver a gene coding for the N-terminal fragment of Shh into the striatum. About a week later, they targeted substantia nigra neurons with the neurotoxin 6-hydroxydopamine (6-OHDA), and then measured neuronal survival. Parallel experiments were carried out with viral delivery of a gene for Gli-1, a transcription factor believed to be translocated to the nucleus further down the Shh pathway, as well as a gene for the nuclear receptor Nurr-1, also critical for maturation of dopaminergic cells. For comparison purposes, a GDNF-expressing vector and a control vector expressing β-galactosidase were used.

Both Shh and Gli-1 managed to protect about 50 percent of the dopaminergic neurons in the substantia nigra from death due to 6-OHDA. By comparison, GDNF protected about 80 percent, and Nurr-1 was no better than the control vector (about 30 percent protected). When the authors looked at the dopaminergic terminal fields in the striatum, they found that GDNF, consistent with previous research, protected some of the axon terminals. Shh and Gli-1 did not have this effect, although they did attenuate atrophy of the surviving dopaminergic neurons, as determined by measuring the size of cell bodies. Again, this effect (82 percent of cell size preserved) was intermediate between the protective effects of GDNF (92 percent) and control (67 percent). Because the toxin produced no behavioral abnormalities, the authors could not assay behavioral effects of the neuroprotection.

Because of the short time frame (animals were sacrificed five weeks after injection of the viral vectors) the authors discount the possibility that the introduced Shh or Gli-1 could have had an effect on adult neurogenesis in the substantia nigra. However, given the evidence that hippocampal adult neurogenesis is regulated by the Shh pathway (see ARF related news story), they suggest that this possible effect of Shh/Gli-1 should also be explored in future experiments (see ARF meeting report by Dora Kovacs).—Hakon Heimer.

Reference:
Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V, Suwelack D, Castro MG, Lowenstein PR. Differentiation and transcription factor gene therapy in experimental Parkinson's disease: sonic hedgehog and gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration. Mol Ther. 2004 Sep;10(3):507-24. Abstract