The molecular regulation of dopamine release and its disregulation in Parkinson’s disease

Not all boutons release dopamine. It remains unclear what regulates the temporal and spatial dynamics of dopamine release. Variable dopamine release defects are found in early Parkinson’s disease, but it remains unclear how dopamine release supports motor function and what defects are pathologically relevant. We study these questions using transgenic mouse models.

Recent advances in imaging tools enabled us to visualize presynaptic calcium dynamics, dopamine release and molecular trafficking in unprecedented resolution. We leverage novel molecular tools to investigate synaptic function and regulation in physiological and in disease relevant conditions.

How do Parkinson’s disease genes cooperate in synaptic pathogenesis

Many Parkinson’s disease genes are enriched in the presynaptic terminal. Whether they each supports an aspect of synaptic function or cooperate to support a common signaling pathway remains unclear. We are interested in exploring the potential convergent signaling of Synj1 with alpha-synuclein, Auxilin1, VPS35, etc. all of which are involved in synaptic membrane trafficking. We aim to understand how these  genes interact and integrate their signaling pathways to culminate in the dysfunction and vulnerability of the nigral dopamine neurons at the presynaptic terminal.

The role of SYNJ1 in age-dependent motor decline

One of the most debilitating aspects of aging is the gradual decline in motor performance, such as coordinated movements and balance. While the cause of motor aging is complex and may rise from changes in multiple peripheral systems, more evidence points to central mechanisms, especially the age-dependent decline in the dopaminergic system. Studies showed that striatal dopamine denervation or reduction in striatal dopamine transporter (DAT) is significantly associated with gait and balance in healthy aging adults. Thus, there’s rising consensus that the aging brain is on the preclinical continuum of Parkinson’s disease (PD). However, it remains to be understood whether PD risk genes contribute to normal age-related motor decline and can be targeted for improving motor abilities in older adults. This project examines the role of a synaptic PD gene, SYNJ1, in age-dependent motor decline through its regulation of DAT.