Genetic and perinatal risk factors for movement disorders

Abstract

Movement disorders, such as Parkinson's disease (PD), Huntington's disease (HD) and cerebral palsy (CP) are debilitating diseases with a great societal impact. These disorders are characterized by damage to the basal ganglia { a set of brain structures involved in motor coordination. The majority of PD cases are idiopathic and thought to be due to the cumulative effect of several genetic and environmental insults over a lifetime on the substantia nigra. In this thesis, I focused on risk factors for basal ganglia damage. I started by screening Caucasian South Africans with PD for variation in the GBA gene, encoding glucocerebrosidase. 12.38% of PD patients and 5.00% of controls in this population group carried a GBA variant, which is comparable to European populations. Common environmental factors in South Africa that could interact with genetic factors to worsen basal ganglia damage were also investigated. Sub-Saharan Africa has a disproportionately high incidence of maternal complications and birth insults. Severe birth insults can lead to life-long disabilities such as CP and mental retardation. But even survivors without visible disability have an increased risk of delayed-onset neurological and psychiatric disorders. I investigated whether perinatal insults or neurodevelopmental disorders could decrease the age-of-onset of HD, a fatal, inherited movement disorder caused by the death of medium spiny neurons in the striatum. Both insults reduced age-of-diagnosis of HD in two large epidemiological studies. In a rat model of preterm perinatal asphyxia (PA), the insult selectively increased nitric oxide production, and thus nitrosidative stress, in the striatum within the frst week after the insult. This could possibly contribute to the phenotype seen in HD patients with perinatal insults. The last part of my thesis focused on therapeutic interventions for PA in the preterm brain. PA causes a massive release of glutamate, which leads to excitotoxicity and neuronal death. I tested whether antagonism of the glutamatergic-NMDA receptors with the anesthetics propofol and iso urane could protect the substantia nigra. Anesthesia was given to the maternal-fetal unit of a sheep model of PA due to umbilical cord occlusion. Propofol anesthesia limited dopaminergic neuron loss, but this was associated with increased tau-phosphorylation in several brain regions which could potentially be detrimental. I further examined the effacacy of multipotent adult progenitor cells (MAPC) therapy for PA in the immature rat brain. The administration of two doses within 24 hours after the insult had a long-lasting effect on gene transcription in the two-week old rat brain. The effects on gene transcription depended on whether the cells were administered through the intranasal or systemic route. The systemic administration had a partial benefficial effect on recognition memory and locomotion in adult rats exposed to PA at birth. In conclusion, this thesis contributes to the body of knowledge on the influence of perinatal and genetic insults on the basal ganglia and the resulting movement disorders, as well as therapeutic strategies to attenuate neuronal loss and functional disabilities.