Loekkegaard, A. | bioRxiv Science

bioRxiv2026

Striatal Dopaminergic Dysfunction Constrains Motor Invigoration in Parkinson's Disease

Bradykinesia is a cardinal motor feature of Parkinson's disease and is characterised by a reduced ability to generate movements with normal speed and force. Although nigrostriatal dopamine loss is regarded as the primary cause, direct human evidence linking dopaminergic degeneration to striatal dysfunction and impaired motor output and vigour remains limited. To investigate this relationship, we developed a grip-force paradigm that quantified movement vigour as the ability to rapidly generate force. Fifty-three individuals with Parkinson's disease, 30 with levodopa-induced dyskinesia and 23 without, and 25 age-matched healthy controls performed the task during 3T functional MRI. Thirty-five patients additionally underwent dopamine transporter PET imaging to assess associations among nigrostriatal dopaminergic integrity, striatal activity and motor performance. Patients with Parkinson's disease showed marked reductions in initial movement vigour accompanied by reduced bilateral putaminal activation during force generation. Lower putaminal dopamine transporter binding was associated with both poorer movement vigour and weaker grip-related putaminal activation during functional MRI, establishing a direct link between nigrostriatal degeneration, impaired striatal recruitment and motor slowing. Functional MRI further revealed reduced reward-related responses in the nucleus accumbens. Across participants, stronger reward-related ventral striatal activity was associated with greater movement vigour, suggesting that motivational processes contribute independently to motor performance. Patients with levodopa-induced dyskinesia exhibited more severe putaminal dopaminergic denervation than patients without dyskinesia but showed no additional impairment of movement vigour or striatal task responses. These findings provide direct in vivo evidence that dorsal nigrostriatal dopaminergic degeneration constrains movement vigour in Parkinson's disease through reduced striatal recruitment during action generation. Impaired reward-related signalling in ventral striatum emerges as an additional, partly independent mechanism influencing motor performance, highlighting distinct motor and motivational contributions to bradykinesia.

neuroscience↗

bioRxiv2020

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DAT in vitro. In vivo, we demonstrate that expression of DAT-K619N in mice and dropsophila imposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and viral overexpression of DAT-K619N in mice show that DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease and neurodegenerative early-onset parkinsonism.

neuroscience↗