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Faculty Profiles

Faculty Research Areas

Office: 210-567-4235
E-mail: ranjan@uthscsa.edu

The genetics of aging in Drosophila and the mechanism of neurotransmitter secretion at the synapse

Overview:  The roots of cognition, behavior, learning and memory are embedded in the brain’s intricate network of neuronal cells and their specialized points of contact, the synapses. Alterations in synaptic signaling underlie a variety of forms of synaptic plasticity associated with learning, memory, and aging and have important roles in the pathogenesis of age-related neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, epilepsy and stroke. My research interests can be divided into two parts a.) What are the molecular mechanisms underlying coordinated behavior, cognition, learning and memory? b.) How are these mechanisms affected by inherited neurological diseases and age-related neurological decline? The focus of my research is to comprehensively elucidate the molecular mechanisms underlying synaptic function, plasticity, and aging. We are combining molecular biology, electrophysiology, imaging and behavioral approaches with Drosophila genetics to investigate the molecular mechanisms involved in neuronal signaling and the underlying changes that cause neurological diseases and neuronal aging.

Research Summary
There are two primary areas of research within my laboratory:

A.)  Genetic dissection of synaptic plasticity and aging:  We are focusing on a provocative G-protein coupled receptor (GPCR), Methuselah, previously shown to increase lifespan.
B.)  Genetic dissection of Ca²⁺-regulated neurotransmitter release:  We are studying the family of proteins containing C2 domains, particularly synaptotagmin, and their roles in membrane traffic. 

A.)  G-Protein dependent synaptic modulation:  In biological systems, physiological responses to extracellular signals are elicited by activation of specific receptor proteins such as G-protein coupled receptors (GPCRs).  Important modulatory roles for GPCRs have been suggested for aging, sleep, synaptic release and other cellular responses.  Adaptive modifications of synaptic efficacy are very important for normal brain functioning and this is accomplished by signaling cascades.  G-protein coupled receptors are important members of these processes. 

Methuselah:  Methuselah mutants were isolated in a screen for mutations affecting resistance to stress and aging.  Methuselah loss-of-function mutations increase lifespan by 35% and also increase stress resistance.  Our analysis of synaptic transmission at the fly larval neuromuscular junction revealed that methuselah mutants have reduced transmitter release and indicate that Methuselah is a modulator of release, perhaps altering a step downstream from Ca²⁺ entry.  We find an interesting paradox in this phenotype: all known synaptic mutants with a reduction in vesicle release die prematurely, unlike Methuselah, which lives longer.  So far the relationship between aging and reduced release has not been addressed.  This is an open and interesting problem currently being investigated in my laboratory.

Recently the ligands for Methuselah have been identified which encode for an ε- subunit of ATP syntheses. Mutations in the ligands also extend lifespan and preliminary analysis suggests that they may modulate presynaptic release like methuselah.  This early analysis provides convincing evidence that Methuselah, a G-protein coupled receptor and other components of its pathway may be very important for synaptic plasticity and subsequently for processes of neuronal aging.  We are using Drosophila as a neuronal aging model to understand the underlying mechanisms.

Ongoing research:      
Our current analysis revolves around four major questions concerning the role of Methuselah in synaptic release in relation to cellular plasticity.  (1) Are the reduction in neurotransmitter release and aging causally related?  (2) How do Methuselah and its ligands control synaptic release and aging?  (3) How do these components interact with synaptic release machinery to modulate aging? (4)  What are the downstream components of the Methuselah pathway regulating vesicle docking/priming?  The systematic analysis of the Methuselah receptor, its ligands and newly found components of this pathway will enable us to understand how this pathway modulates the synapse.  We are analyzing the known components and at the same time looking for new molecules by genetic interaction and screens.

B.)  Ca²⁺-triggered vesicle fusion:  Since the discovery that Ca²⁺ is essential for fast, regulated neurotransmitter release, neurobiologists have been in search of the relevant molecules that sense the Ca²⁺ flux.  In the past decade synaptic proteins such as SNAREs and Synaptotagmin I were shown to be central to the calcium triggered fusion.  Yet despite considerable effort, the definitive roles of Synaptotagmin I and other key synaptic proteins have not been determined.  The problem is made more complex by the fact that Synaptotagmins are members of a large family, most of which bind to Ca²⁺.  Initial analysis suggests that family members may function in a combinatorial fashion to sense Ca²⁺ at a given synapse.  We are exploring the role of individual synaptotagmin isoforms and the interrelationship between different isoforms to understand their synaptic functions.  Beside synaptotagmins, we are in the process of analyzing novel synaptic genes and have begun genetic screens to identify additional components that function in synaptic transmission by directly screening for electrophysiological defects.

Summary:  To comprehensively address the issue of synaptic vesicle exocytosis and its modulation, we have chosen Drosophila as a model system which can be easily manipulated at multiple levels.  I plan to combine genetics with molecular biology, electrophysiology, imaging and behavior.  Systematic genetic dissection of these different genes will help in understanding their individual and combinatorial roles in synaptic plasticity and aging.

Selected Publications

Interactions between members of the Drosophila exocyst complex and characterization of a sec6 mutant. M. Murthy, Ravi Ranjan, N. Denef, T. Schupbach and Thomas L. Schwarz. J Cell Sci. 2005 Mar 15; 118(Pt 6):1139-50. Epub 2005 Feb.

Presynaptic Regulation of Neurotransmission in Drosophila by the G Protein-Coupled Receptor Methuselah Wei Song*, Ravi Ranjan*, Peter Bronk, Ken Dawson-Scully, Leo Marin, Laurent Seroude, YiJyun Lin, Zhiping Nie, Harold L. Atwood, Seymour Benzer and Konrad E. Zinsmaier. Neuron, 2002, Vol. 36(1) 105-119. (*Equal contribution).

Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A Domain Iain M. Robinson*, Ravi Ranjan* and Thomas L. Schwarz Nature, 2002, Vol. 418(6895):336-40. (*Equal contribution).

Drosophila Liprin- and the Receptor Phosphatase Dlar Control Synapse Morphogenesis Nancy Kaufmann, Jamin DeProto, Ravi Ranjan, Hong Wan, and David Van Vactor. Neuron, 2002, Vol. 34: 27-38.

Overexpression of Cysteine-String Proteins in Drosophila Reveals Interactions with Syntaxin Zhiping Nie*, Ravi Ranjan*, Julia Wenniger, Susie N. Hong, Peter Bronk, and Konrad E. Zinsmaier. The Journal of Neuroscience, 1999, Vol. 19: 10280-88. (*Equal contribution).

Cysteine String Protein Is Required for Calcium Secretion Coupling of Evoked Neurotransmission in Drosophila But Not for Vesicle Recycling Ravi Ranjan, P. Bronk, and K. E. Zinsmaier. The Journal of Neuroscience, 1998, Vol. 18(3): 956-964.