The role of Synaptojanin1 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 (murine Synj1), which encodes a lipid phosphatase essential for synaptic membrane trafficking. Our recent studies showed that the dopaminergic synapse rely on Synj1 for axonal surface DAT maintenance. Accordingly, Synj1 deficient mice exhibit lack of surface DAT availability and locomotor deficits, suggesting a Synj1-DAT signaling axis involved in motor control. Our preliminary study showed that loss of Synj1 not only occurs in pathological conditions but is also present during normal aging in both humans and mice. We further found age-dependent loss of Synj1 in striatal dopaminergic terminals, suggesting a potentially pivotal role of Synj1 in age-dependent changes in DAT and motor control. We will test the hypothesis that elevating Synj1 level in DA neurons of adult mice could help improve motor performance and increase striatal/axonal DAT surface expression. We will assess two functional mutants of Synj1 to be compared with WT Synj1, which is expected to bring insights to lipid signaling mechanisms underlie motor control. In Aim 1, we will examine locomotor behavior in an older and a younger cohort to determine whether motor decline during aging can be improved or prevented by Cre-dependent Synj1 expression in DA neurons. In Aim 2, we will determine whether striatal/axonal DAT expression and function can be increased by Cre-dependent Synj1 expression in DA neurons using a combination of biochemical and imaging approaches. Successful completion of the project will reveal the causal role of Synj1 in motor decline during aging and the potential DAT-mediated mechanism and downstream lipid signaling contributing to in this effect. More importantly, it will provide the rationale and proof- of-concept evidence for elevating Synj1 expression as a therapy to improve motor ability in older adults. Project Number: 1R21AG099384-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ping-Yue Pan | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $431,750 | Activity Code: R21 | Study Section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11388089