Floating Brains

Please find our guests for this series by alphabetic order by surname

Dario Alesso

WCNeuro S3, EP6 – Parkinson’s with Professor Dario Alessi

Much of Dario’s current work is focused on deciphering how autosomal dominant missense mutations that hyper-activate the LRRK2 protein kinase, predispose humans to Parkinson’s disease.

LRRK2 mutations are the most frequent cause of inherited Parkinson’s disease, accounting for at least 5% of familial and 1-2% of idiopathic Parkinson’s disease. Parkinson’s disease affects an estimated 7 million people worldwide and all attempts to slow the progression of Parkinson’s have thus far failed.

The cardinal symptoms, shaking, rigidity, and slowness of movement arise from degeneration of dopaminergic neurons located within the substantia nigra. Dementia and behavioural disorders are unfortunately also common in the advanced stages of the disease.

The therapeutic efficacy of LRRK2 inhibitors are currently being tested in clinical trials. They represent one of the most promising therapeutic strategies currently under evaluation for slowing Parkinson’s disease progression, at least for patients possessing LRRK2 mutations.

Dario’s research focuses on understanding how LRRK2 is regulated and functions and how mutations in this protein kinase lead to Parkinson’s disease.
Dario’s lab in collaboration with Matthias Mann showed that LRRK2 phosphorylates a subgroup of Rab proteins (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab29, Rab35, and Rab43) at a conserved Thr/Ser residue (Thr73 for Rab10), located at the centre of the effector binding switch-II motif [1, 2].

Consistent with Rab proteins comprising disease-relevant substrates, Dario’s lab have demonstrated that all established pathogenic mutations enhance LRRK2 mediated Rab protein phosphorylation in a manner that is blocked by diverse LRRK2 inhibitors [1-3].
LRRK2 phosphorylation of Rab proteins blocks the ability of Rab proteins to interact with cognate effectors such as GDI and guanine nucleotide exchange factors, thereby trapping the phosphorylated Rab protein in the GTP bound state on the membrane where it has been phosphorylated [1, 2].

Recent work identified a novel group of effectors including RILPL1, RILPL2, JIP3 and JIP4 that bind preferentially to LRRK2 phosphorylated Rab8 and Rab10 [2, 4]. The work of Dario’s collaborator Suzanne Pfeffer at Stanford University (https://biochemistry.stanford.edu/suzanne-pfeffer) has revealed that LRRK2 phosphorylated Rab8A and Rab10, in complex with RILPL1/RILPL2, inhibit the formation of primary cilia that are implicated in controlling a Sonic hedgehog-driven neuroprotective pathway that could provide a mechanism by which LRRK2 is linked to Parkinson’s disease [5].

Dario’s research has also revealed that other proteins encoded by genes implicated in Parkinson’s disease including Rab29 [6] and VPS35 [7], regulate phosphorylation of Rab proteins via LRRK2. They have also developed new methods to interrogate LRRK2 pathway activity in cell and mouse models [8] as well as humans [9]. They have recently identified a novel protein phosphatase termed PPM1H that counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins [10].

Key gaps remain in our knowledge of how LRRK2 is regulated and functions that Dario’s laboratory is working hard to address. These include understanding how Rab29, VPS35, the immune system, and other Parkinson’s disease genes and risk variants impact on the LRRK2 pathway. Individual functions of the different Rab proteins that are phosphorylated by LRRK2 and the effectors that interact with these after they are phosphorylated need to be identified, as well as establishing how this impacts downstream biology. It will be important to comprehend what are the most relevant Rab substrates that link LRRK2 to Parkinson’s disease. Much evidence suggests that LRRK2 regulates the endo-lysosomes through an unknown pathway that Dario’s lab aims to decipher. Understanding how PPM1H and other protein phosphatases control the LRRK2 pathway is also an important question.

Gary Donohoe

WCNeuro S3, EP9 – Psychosis and schizophrenia part one with Professor Gary Donohoe

Gary’s research group, the CogGene group has strong collaborative ties with both the neuropsychiatric research group at TCD (with Prof. Aiden Covin & Prof Michael Gill) and the clinical neuroimaging group at NUIG (with Prof Colm McDonald and Dr. Dara Canon). The group studies how brain structure and function are affected by genetic risk factors for psychosis using neuropsychology, MRI and EEG.

Aspects of brain structure, such as brain volume and white matter integrity, and brain functions, such as cortical activations that occur during information processing, are likely to mediate the effects of genetic risk variants on illness. In what is often described as an ’intermediate phenotype’ or ‘endophenotype’ approach, studying these brain based ’phenotypes’ may help bring us closer to the mechanism of gene activity so as to understand the broader illness phenotype. To do this our work draws on neuropsychological, electrophysiological, and neuro-imaging techniques for investigating the role of gene function at the level of individual brain systems.This work has led to a number of important insights into newly discovered risk genes for psychosis. As part of this work the group is actively involved in developing psychological therapies for major mental health disorders, including therapies that address cognitive deficits in schizophrenia.

The group participates in several international consortia focused on the genetics of psychosis and the genetics of brain structure and function, including the ENIGMA consortium, the COGENT consortium, the GENUS consortium, the Psyscan consortium, and the Psychiatric Genomics Consortium (PGC).

The work of the Cognitive genetics and cognitive therapy group is generously funded by several national and international sources, including Science Foundation Ireland (SFI), The health Research Board (HRB), and the National Institute of Mental Health (NIMH).

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Julianne Flanigan

WCNeuro S3, EP8 – PTSD and domestic abuse with Dr Julianne Flanigan

Dr. Flanagan is an Assistant Professor in the Addiction Sciences Division of the Department of Psychiatry and Behavioral Sciences. She received a B.A. in psychology at the University of Vermont in 2003 and an M.A. and Ph.D. in clinical psychology at the University of Tennessee 2011. She completed her clinical psychology internship training at the Seattle VA and a NIDA-funded postdoctoral fellowship at the Yale University School of Medicine.

Seth Grant

WCNeuro S3, EP5 – Neurons are computers with Professor Seth Grant

The long-term aim is to understand the fundamental mechanisms of behaviour and how these mechanisms are involved in brain disease.

The research has focussed on the study of genes and proteins that control the synapses between nerve cells. Multiprotein machines comprising many different protein components are responsible for basic innate and learned behaviours and dysfunction in many brain diseases.

Recent work shows that these mechanisms are conserved between mice and humans opening new avenues for diagnosis and therapeutic discoveries. The Genes to Cognition programme has generated a large amount of data and tools that are freely available.

John Hardy

WCNeuro S3, EP7 – Alzheimer’s with Professor John Hardy

My research interests are in the genetic analysis of disease. Historically, we have worked on the genetic analysis of Alzheimer’s disease and other dementias. More recently, we have worked on Parkinson’s disease and other movement disorders and, most recently on motor neuron disease. Our early studies were on mendelian forms of disease and these studies continue, but an increasing focus has been on the genetic analysis of complex traits related to disease. Additionally, this latter analysis has made us increasingly interested in population genetics because the risk variants for human traits are likely to be different in different racial groups.

In all cases our intention is to develop an understanding of the underlying genetics of a disorder so we can work with those making cellular and animal models of the disease to help, both in the understanding of disease mechanisms and to help in the search for treatments. In this regard, we therefore have three types of collaborations: collaborations with clinicians who treat patients with disease, especially colleagues at the Institute of Neurology, but also elsewhere, collaborations with other geneticists to collaboratively analyse such patient material, and collaborations with cell biologists and transgenic mice people to enable them to build good models of disease.

Alan Jasanoff

WCNeuro S3, EP4 – Improve my fMRI with Professor Alan Jasanoff

The Jasanoff laboratory is developing a new generation of functional magnetic resonance imaging (fMRI) methods to study the neural mechanisms of behavior. Its principal focus is on the design and application of new contrast agents that may help define spatiotemporal patterns of neural activity with far better precision and resolution than current techniques allow. Experiments using the new agents will combine the specificity of cellular neuroimaging with the whole brain coverage and noninvasiveness of conventional fMRI. Introduction of these technologies will have far-reaching consequences in neuroscience, because the new imaging methods will be applicable to studies of any neural system in vivo. The Lab’s goal is to use the methods to build explanatory models of neural network function in animals, with current emphasis on brain circuitry involved in instrumental learning behaviour.

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James Kesby

WCNeuro S3 EP10 – Psychosis and schizophrenia part two with Dr James Kesby

My research focusses on the neurochemical control of behaviour, particularly that involved in psychosis, schizophrenia and addiction. Through the investigation of developing dopamine pathways in experimental animal models my work aims to understand the abnormal circuitry in human neuropsychiatric disorders. Animal models provide an avenue to explore function and neurodevelopment using techniques that cannot be used in human subjects. However, interacting directly with clinicians and performing translational studies are key to putting these facts into context. I work closely with clinical researchers focussed on the daunting task of understanding, identifying and treating early psychosis. This cross-disciplinary research collaboration continues to pursue better outcomes for people suffering from mental illness.

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Robert Malenka

WCNeuro S3, EP3 – How cells respond to information with Professor Rob Malenka

Long-lasting activity-dependent changes in the efficacy of synaptic transmission play an important role in the development of neural circuits and may mediate many forms of learning and memory. Work from my laboratory over the last 10 years has demonstrated that there are a variety of related but mechanistically distinct forms of synaptic plasticity. A major goal of my laboratory is to elucidate both the specific molecular events that are responsible for the triggering of these various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. To accomplish this we use cellular electrophysiological recording techniques to examine synaptic plasticity in a variety of different in vitro preparations including thin slices of various regions of the rodent brain and primary neurons in culture. We also use cell biological and molecular techniques to examine the activity-dependent modulation of neurotransmitter receptors and to express dominant negative forms of various synaptic proteins so that their exact functions can be determined. An additional complementary approach has involved examining synaptic physiology and synaptic plasticity in various mutant mouse lines lacking specific synaptic proteins.

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Vidhya Rangaraju

WCNeuro S3, EP2 – How neurons use energy part 2 with Dr Vidhya Rangaraju

Our data indicates that mitochondria may serve as organizers of local compartments of energy within dendrites. Recent technological advances give us unprecedented ways to study and manipulate mitochondria within individual cell-types and subcellular compartments.

The overarching goal of our research group is to dissect mitochondrial function and its optimization in neuronal compartments. We focus on the proteins that comprise and regulate mitochondria and the other energy supplies such as glycolysis and glial-neuronal networks in different neuronal compartments. We utilize state-of-the-art imaging, advanced proteomics and translatomics technology. We plan to apply our findings to disease model systems for Parkinson’s and ALS where the underlying causes of mitochondrial protein dysfunction are mostly unknown.

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Tim Ryan

WCNeuro S3, EP1 – How neurons use energy part one with Dr Tim Ryan

The focus of this lab is the study of the molecular basis of synaptic transmission in the mammalian brain. Our primary interests lie in understanding the regulation of vesicle traffic in presynaptic terminals, and how this traffic impacts presynaptic function. Synaptic terminals are specialized cellular structures that carry out carefully orchestrated vesicle trafficking through the interplay of molecular machines. Modulation of synaptic function almost certainly relies on changing the efficiency of one of many of these trafficking steps. Similarly, synaptic dysfunction could easily arise from loss of proper regulation of these steps. We use biophysical tools to characterize the molecular machinery as it functions in living synapses, ultimately always asking the question of how synapses work. We use many types of optical assays in combination with molecular, genetic and chemical tools to determine the molecular basis of various steps of the vesicle cycle as well as the roles of specific proteins that are enriched in the presynaptic terminal. In recent years we have been addressing how endocytosis is regulated at nerve terminals as well as how vesicles are clustered and mobilized for secretion upon action potential firing. The lab continuously develops new assays and approaches to address these questions. Through these studies, we hope to gain insight into how information is controlled at the synaptic level in both normal and diseased states of brain function.