Tyrosine Hydroxylase Deficiency Impairs TH Axonal Transport, Brain Function, and Neuronal Plasticity

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder caused by biallelic pathogenic variants in the Th gene, leading to a deficiency in the rate-limiting enzyme for the synthesis of dopamine (DA) and other catecholamine neurotransmitters. THD is associated with dystonia and infantile parkinsonism with a broad and complex spectrum and variable response to l-Dopa therapy. TH1-p.R202H is a frequent THD variant that affects TH stability and activity. The Th knock-in (Th-ki) mice with the equivalent mutation (Th-p.R203H) present reduced TH and DA levels, biological and molecular alterations, different phosphorylation patterns and altered distribution of dopaminergic markers relative to wild-type mice. Th-ki mice displayed significantly reduced TH, especially in the striatum, but also in the cortex, olfactory bulb, cerebellum, substantia nigra, globus pallidus, and spinal cord, a decrease that is not associated with dopaminergic neuronal degeneration. No changes were observed in Th-mRNA expression, and the decreased level of TH in the concrete brain areas in Th-ki mice appears to be due to defective TH protein axonal transport. Moreover, we characterized the development of dopaminergic neurons in the substantia nigra and neuronal plasticity in various brain regions. Our results indicated that alterations in TH expression within specific striatal GABAergic interneurons due to TH deficiency may potentially disrupt the balance of inhibitory neurotransmission in the striatum. Overall, our findings demonstrate that TH deficiency disrupts striatal inhibitory circuitry and triggers compensatory neuronal plasticity, without causing neuronal degeneration.