Welcome to the Chandra Lab!
The Chandra lab explores two related themes: synaptic biology and neurodegeneration. Synapses, connections between neurons, need to be maintained throughout the life of an organism to provide for normal brain functions and behaviors. In the healthy brain, the majority of synapses are largely stable throughout life. However, in late-onset neurodegenerative disorders, synaptic dysfunction and synapse loss are early, pivotal events. In these devastating diseases, synaptic changes occur in the prodromal stage of disease, prior to neuronal cell death. Thus, elucidating the mechanisms by which synapses are maintained is of high biomedical importance. This is the focus of our research. My laboratory studies how synapses are normally maintained and how disruption in these processes results in neurodegenerative disorders.
Recent work, including from my group, has shown that local synaptic protein homeostasis (proteostasis) mechanisms are essential for maintaining the structure and functionality of synapses. Emerging genetic data strongly support the tenet that synaptic proteostasis is disrupted in late-onset neurodegenerative diseases. My group currently investigates two related neurodegenerative diseases, namely Parkinson’s disease (PD) and neuronal ceroid lipofuscinosis (NCL). Our central hypothesis is that PD and NCL are diseases of the synapse, particularly, diseases of presynaptic proteostasis and dysfunction. The findings that α-synuclein, a key protein in the pathophysiology of PD, oligomerizes/aggregates at the presynaptic terminal and the three known presynaptic co-chaperones, CSPα, auxilin, and RME-8 are mutated in NCL and PD, respectively, strongly support our hypothesis. Furthermore, our current progress on investigating α-synuclein, synaptic chaperones, as well as degradative pathways is in line with this hypothesis. To elucidate synapse maintenance mechanisms and understand the early, synaptic events of PD and NCL, we use mouse models and human induced pluripotent stem cell (iPSC) derived neuronal models in conjunction with proteomics, cell biology, physiology, and functional imaging.