Faculty Bibliography

Tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), expressed in normal astrocytes, were used in combination for the treatment of Parkinson's disease (PD) symptoms in a rat model. Normal neonatal rat astrocytes were co-transfected with a vector expressing BDNF (AAVBDNF) and a retroviral vector expressing TH (termed TH-BDNF-DA(+) cells), and then implanted into the striatum of PD rats induced by 6-hydroxydopamine. TH-BDNF-DA(+) cells compensated for a severe insufficiency of endogenous dopaminergic neurons in the PD rats, resulting in a significant improvement of PD symptoms. The decrease in the rotational rate of PD rats implanted with TH-BDNF-DA(+) cells was more marked than that in PD rats implanted with normal astrocytes expressing either TH or BDNF alone (termed TH(+) and BDNF(+) cells, P<0.01 and 0.001, respectively), and suggested a synergistic effect between TH and BDNF. In contrast, the rotational rate was not altered from the baseline in PD rats without treatment or implanted with parental rat astrocytes alone (P>0.05). BDNF protected the dopaminergic neurons from apoptosis induced by 6-hydroxydopamine, and significantly increased the long-term survival of TH-positive cells in the striatum.Our data indicate that the combined use of TH and BDNF has a synergistic therapeutic effect, and is more efficient for the treatment of PD than a single gene therapy using either TH or BDNF alone

Among Ashkenazi Jewish individuals with mucolipidosis IV (ML IV), two mutations in the ML IV gene, IVS3-1A --> G and delEX1-EX7, account for more than 95% of disease alleles. The reported method of genotyping for the delEX1-EX7 mutation involves a cumbersome multistep procedure. In the present study, a new simplified one-step procedure is described that detects this mutation in both patients and carriers. An improved procedure is also described for detection of the IVS3-1A --> G mutation. Using these improved procedures, we have characterized the ML IV mutant alleles in 27 patients and 95 of their relatives from 22 families, and in 123 unrelated and unaffected Ashkenazi Jewish controls. Of the 27 ML IV patients, 16 patients (59.3%) were found to be homozygous for the IVS3-1A --> G mutation and 1 patient (3.7%) homozygous for the delEX1-EX7 mutation. Additionally, 9 patients (33.3%) were compound heterozygotes for IVS3-1A --> G/delEX1-EX7. Among the 123 Ashkenazi Jewish controls, two individuals were identified as heteroallelic with one IVS3-1A --> G mutation (carrier frequency: approximately 1 in 61); none showed the delEX1-EX7 mutation. The modifications described here provide a more facile means of genotyping patients and carriers and expand the possibilities for screening at-risk populations