CHARACTERISATION OF THE HUMAN SUBSTANTIA NIGRA IN CASES OF X-LINKED DYSTONIA PARKINSONISM

X-linked Dystonia Parkinsonism (XDP) is a rare X-linked recessive neurodegenerative movement disorder broadly categorised by dystonia and parkinsonism symptomatology. Basal ganglia dysfunction, in particular a mosaic-like pattern of striatal projection neuron (SPN) loss, is thought to underlie XDP pathophysiology. The substantia nigra (SN), part of the basal ganglia network, is a key region which not only receives neural input from SPNs in the striatum but also projects to the striatum to influence its activity. Given that the SN is widely implicated in Parkinson’s disease, a condition which shares symptoms with XDP, the SN serves as a critical region for investigating XDP pathophysiology. Free-floating histological and fluorescent immunohistochemistry coupled with high-throughput image analysis techniques were performed in the SN of 12 post-mortem XDP cases and compared with age-matched neurologically normal controls. Our findings demonstrate a 38% loss of dopaminergic neuromelanin-expressing cells in XDP cases based on quantification of neuromelanin. We also report a 68% loss of tyrosine hydroxylase⁺ dopaminergic neurons in XDP cases. We also found an extensive 80% reduction of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa), 62% reduction in substance P and 48% reduction in enkephalin in the XDP SN. These reductions suggest dysregulation of both nigrostriatal and striatonigral connectivity in the XDP brain and point towards dopaminergic dysfunction in the XDP SN. Collectively, these findings strongly implicate the SN as a key nucleus to be studied in tandem with the striatum to unravel the neuropathological signature of XDP, reinforcing its consideration as a therapeutically relevant target.