AADCd PhD - Substrate Accumulation in AADC deficiency

2007 - 2010

Dr George Allen

AADC is responsible for the production of two neurotransmitters called serotonin and dopamine. To make these neurotransmitters AADC uses starting materials known as “substrates”. The substrate for serotonin production is 5-HTP and the substrate for dopamine production is L-dopa. In AADC deficiency there is a block in the production of serotonin and dopamine. The block in production means that 5-HTP and L-dopa don’t have anywhere to go and so like traffic at roadworks they start to accumulate. So patients with AADC deficiency are exposed to much higher levels of these chemicals than would normally be found in the brain. This study investigated whether accumulation of L-dopa or 5-HTP could cause damage to cells similar to those found in the brain.

At high levels L-dopa was found to be damaging to cells, however much of the L-dopa in the brain of AADCd patients is converted to 3-O-methyldopa. 3-O-methyldopa was not found to be damaging even at very high amounts. This suggests that the conversion of L-dopa to 3-O-methyldopa may be an important protective strategy. 5-HTP was also found to be mildly damaging at very high levels. The amount of L-dopa or 5-HTP required for damage to occur was more than would be expected in the brain of patients with AADC deficiency. The levels were certainly much higher than the amounts measured in the CSF of AADCd patients. This suggests that substrate accumulation may not be damaging in AADC deficiency although longer term studies are needed to confirm this.

During normal metabolism the brain produces “reactive oxygen species” that need to be carefully controlled to prevent them causing damage. One way that these reactive oxygen species are controlled is with a chemical called glutathione that acts to protect brain cells from damage. During this PhD project it was found that L-dopa could increase the amount of glutathione in brain cells. However, in cells that had no AADC or had their AADC activity inhibited L-dopa was unable to increase glutathione. The L-dopa needed to be converted to dopamine by AADC in order to increase the amount of the protective chemical glutathione. This result indicates that glutathione levels could be changed in patients with AADC deficiency and this could be an important area for future research.

The plasma AADC activity diagnostic test and vitamin B6 status

One of the most important tasks during this PhD project was the establishing of a blood plasma test for AADC deficiency in the UK. The test measures the activity of AADC in patient plasma and the test is now offered as a diagnostic service within the Neurometabolic Unit at the National Hospital for Neurology and Neurosurgery in London. During the three year period of the PhD this test was used to aid the diagnosis of six new patients with AADC deficiency. Interestingly, using this test AADC activity was also found to be low in two patients diagnosed with a related disorder called PNPO deficiency. This disorder leads to a loss of the AADC cofactor pyridoxal 5’-phosphate (vitamin B6) and although the cofactor was added back in during the test AADC activity remained low, suggesting the actual amount of active AADC was decreased. To further investigate this vitamin B6 deficiency was modelled in cells grown in culture. Like in patients, vitamin B6 deficiency in cells led to a loss of active AADC protein and the level of loss correlated very well with the decrease in vitamin B6. Patients with AADC deficiency do still have some AADC activity although this activity is very low. This investigation demonstrates the potential importance of maintaining vitamin B6 levels in patients in order to prevent further loss of already low AADC activity.

The AADC Research Trust awarded 80,000 GBP to fully fund this PhD project. The project was conducted by George Allen and was supervised by Prof. Simon Heales and Dr John Land. The work was undertaken at the UCL Institute of Neurology from October 2007 until November 2010.

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