Investigator:
Nirmal Kumar, PhD
Name of Institution:
Rutgers, The State University of New Jersey
Project Title:
Synaptojanin-1 and VPS35 Interaction in Presynaptic Vulnerability
Investigator Bio:
Dr. Nirmal Kumar is a Postdoctoral Associate in the Department of Neuroscience and Cell Biology at Rutgers University, working in the laboratory of Dr. Pingyue Pan. His research focuses on identifying early molecular mechanisms in Parkinson’s disease (PD) that lead to presynaptic dysfunction, dopamine imbalance, and ultimately dopamine neuron loss. He is particularly interested in how synapses are organized and maintained for effective neurotransmission – and how their disruption contributes to the early stages of PD.
Dr. Kumar earned his PhD in 2024 from the University of North Dakota under the mentorship of Dr. Jonathan D. Geiger. His doctoral research investigated how endolysosomal dysfunction, iron imbalance, and oxidative stress converge to drive neuronal injury in conditions such as HIV-associated neurocognitive disorders and iron overload. His work uncovered a novel mechanism linking early endolysosome redox disruption to neuronal damage.
In his current research, Dr. Kumar uses both cellular models and genetically modified mice to identify molecular targets that enable early therapeutic intervention of PD and help preserve dopamine system function before neurodegeneration becomes irreversible.
Objectives/Background: This project will study how two genes linked to PD – SYNJ1 and VPS35 – work together to regulate dopamine transport and affect movement. In PD, some of the first problems happen at connections between brain cells called synapses where dopamine is released, long before brain cells start to die. Scientists don’t yet fully understand why and how this happens. These early synaptic defects impair dopamine signaling and may contribute to movement problems. Many PD risk genes function at synapses, including SYNJ1 and VPS35, which help regulate the distribution of proteins needed for dopamine release and recycling. This project focuses on the dopamine transporter (DAT), a key synaptic protein that fine-tunes dopamine signaling. Reduced DAT at synapses is a consistent early feature of PD, but the pathways controlling its distribution remain poorly understood. This study will examine how SYNJ1 and VPS35 work together to regulate DAT distribution, dopamine balance, and movement, and will test whether boosting VPS35 can restore these processes when SYNJ1 is lost.
Methods/Design:
This study will use both neuronal cultures and genetically engineered mice in which the SYNJ1 gene is selectively deleted in dopamine-producing neurons. We will grow cells in culture and study dopamine neurons isolated from the mouse midbrain to test how SYNJ1 and VPS35 work together to control DAT levels. We will also use molecular and biochemical tools to examine how disease-related mutations in SYNJ1 disrupt its ability to interact with VPS35, leading to impaired DAT regulation and dopamine signaling. In mice, we will use gene therapy to boost or reduce VPS35 levels and assess whether this restores dopamine levels and movement – or whether the loss of VPS35 worsens these outcomes. Together, these approaches will help us understand how SYNJ1 and VPS35 normally cooperate at brain connections involving dopamine and how their disruption contributes to dopamine imbalance and movement problems in PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A major barrier to developing better treatments for PD is our limited understanding of the earliest changes in bran cell connections when treatment might work best. One key early change is the loss of the dopamine transporter (DAT), a protein that helps control dopamine levels. This loss often occurs before symptoms appear and may contribute to dopamine imbalance and movement problems. Yet what causes this early DAT loss – and whether it can be therapeutically corrected – remains unknown. This project investigates a novel pathway involving two PD risk genes – SYNJ1 and VPS35 – which may work together to control DAT distribution and dopamine balance. It also examines VPS35-based gene therapy as a potential early intervention to restore DAT, preserve cellular connections, and improve movement. Insights from this work could help create new treatments aimed at the earliest brain changes in PD, which might slow or even prevent disease progression.