Welcome to Gabrielle Rudenko's Research LabSynapses, Neurological Disorders, Protein Structure and Function
"Step-by-step" - a feature story by SBgrid Consortium.
Research
There are an estimated hundred billion neurons in the human brain and
they are connected to each other via physical contact points called
synapses. Synapses enable neurons to communicate with each other. The
hundreds of trillions of synapses in our brain establish neural
circuitries that guide how we think, move and feel. More than a thousand
different proteins are found at synapses and they form complex protein
networks. Paradoxically, synapses are both insoluble and yet also
plastic. On the one hand, synapses are isolated biochemically as the
'triton-insoluble' fraction. Yet on the other hand, in vivo, synapses
come and go. Synapses grow 'weaker' and 'stronger', as their adhesive
properties and their ability to transmit signals change. Significantly,
properties of synapses also appear to change as a function of their
activity. External stimuli such as events triggering memory and learning,
stress, and exposure to chemicals such as drugs of abuse,
anti-depressants and anti-psychotics, all seem to affect synapses and
the connections they form. Many different neuropsychiatric disorders
and neurodegenerative disorders are increasingly being referred to as
'synaptopathies', emphasizing the role of disrupted synaptic structure
and function in the pathogenesis of these disorders. By unraveling how
the many different synaptic proteins interact with each other and form
complex protein networks, we hope to not only gain fundamental insight
into how neurons communicate with each other enabling the brain to
function, but also to discover new potential therapeutic targets.
Our laboratory is particularly fascinated by the complex protein
networks in the synaptic cleft found at chemical synapses, i.e. the
250 space between the 'pre-synaptic' membrane which hosts the
exocytosis machinery for synaptic vesicles and the 'post-synaptic'
membrane which hosts machinery responding to the transmitted chemical
signals. We are studying a number of synaptic adhesion molecules and
synaptic organizers to understand their role in mediating synapse
formation, maintenance, and plasticity. One family of synaptic adhesion
molecules that we have studied extensively is the family of neurexins.
Neurexins play a role in synapse organization and adhesion. Mutations
and lesions in neurexins have recently been implicated in autism
spectrum disorder, schizophrenia and mental retardation. Excitingly,
not only neurexins, but also many of their direct protein partners in
the synaptic cleft are implicated in these diseases as well (Fig. 1).
Neurexins and their partners must touch fundamental biological processes
that are involved in the pathogenesis of these disorders, but it is not
clear which processes these are and the exact role that neurexins and
their partners play in these processes.
Our laboratory is working to understand on a molecular level how
neurexins, their partners, as well as a number of other synaptic
organizers recognize, bind, and arrange different synaptic partners in
the synaptic cleft impacting synaptic function. By understanding the
molecular mechanisms of these molecules, we will be able to not only
further delineate their role at synapses but also understand why these
molecules, when disrupted, contribute to neurological disorders.
We use biochemical and biophysical techniques as well as protein crystallography (Fig. 2).
Our laboratory is particularly fascinated by the complex protein
networks in the synaptic cleft found at chemical synapses, i.e. the
250 space between the 'pre-synaptic' membrane which hosts the
exocytosis machinery for synaptic vesicles and the 'post-synaptic'
membrane which hosts machinery responding to the transmitted chemical
signals. We are studying a number of synaptic adhesion molecules and
synaptic organizers to understand their role in mediating synapse
formation, maintenance, and plasticity. One family of synaptic adhesion
molecules that we have studied extensively is the family of neurexins.
Neurexins play a role in synapse organization and adhesion. Mutations
and lesions in neurexins have recently been implicated in autism
spectrum disorder, schizophrenia and mental retardation. Excitingly,
not only neurexins, but also many of their direct protein partners in
the synaptic cleft are implicated in these diseases as well (Fig. 1).
Neurexins and their partners must touch fundamental biological processes
that are involved in the pathogenesis of these disorders, but it is not
clear which processes these are and the exact role that neurexins and
their partners play in these processes.
