Time filter

Source Type

Lausanne, Switzerland

Dhungel N.,Stanford University | Eleuteri S.,University of California at San Diego | Li L.-B.,Stanford University | Li L.-B.,Howard Hughes Medical Institute | And 13 more authors.
Neuron | Year: 2015

Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and α-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation. © 2015 Elsevier Inc. Source

Schneggenburger R.,Brain Mind Institute | Rosenmund C.,Charite - Medical University of Berlin
Nature Neuroscience | Year: 2015

The relationship between transmitter release evoked by action potentials and spontaneous release has fascinated neuroscientists for half a century, and separate biological roles for spontaneous release are emerging. Nevertheless, separate functions for spontaneous and Ca 2+ -evoked release do not necessarily indicate different origins of these two manifestations of vesicular fusion. Here we review how Ca 2+ regulates evoked and spontaneous release, emphasizing that Ca 2+ can briefly increase vesicle fusion rates one-millionfold above spontaneous rates. This high dynamic range suggests that docked and readily releasable pool (RRP) vesicles might be protected against spontaneous release while also being immediately available for ultrafast Ca 2+ -evoked release. Molecular mechanisms for such release clamping of highly fusogenic RRP vesicles are increasingly investigated. Thus, we view spontaneous release as a consequence of the highly release-competent state of a standing pool of RRP vesicles, which is molecularly fine-tuned to control spontaneous release. © 2015 Nature America, Inc. Source

Loued-Khenissi L.,Brain Mind Institute | Preuschoff K.,University of Geneva
Current Opinion in Neurology | Year: 2015

Purpose of review Mild cognitive impairment (MCI) is a comorbid factor in Parkinson's disease. The aim of this review is to examine the recent neuroimaging findings in the search for Parkinson's disease MCI (PD-MCI) biomarkers to gain insight on whether MCI and specific cognitive deficits in Parkinson's disease implicate striatal dopamine or another system. Recent findings The evidence implicates a diffuse pathophysiology in PD-MCI rather than acute dopaminergic involvement. On the one hand, performance in specific cognitive domains, notably in set-shifting and learning, appears to vary with dopaminergic status. On the other hand, motivational states in Parkinson's disease along with their behavioral and physiological indices suggest a noradrenergic contribution to cognitive deficits in Parkinson's disease. Finally, Parkinson's disease's pattern of neurodegeneration offers an avenue for continued research in nigrostriatal dopamine's role in distinct behaviors, as well as the specification of dorsal and ventral striatal functions. Summary The search for PD-MCI biomarkers has employed an array of neuroimaging techniques, but still yields divergent findings. This may be due in part to MCI's broad definition, encompassing heterogeneous cognitive domains, only some of which are affected in Parkinson's disease. Most domains falling under the MCI umbrella include fronto-dependent executive functions, whereas others, notably learning, rely on the basal ganglia. Given the deterioration of the nigrostriatal dopaminergic system in Parkinson's disease, it has been the prime target of PD-MCI investigation. By testing well defined cognitive deficits in Parkinson's disease, distinct functions can be attributed to specific neural systems, overcoming conflicting results on PD-MCI. Apart from dopamine, other systems such as the neurovascular or noradrenergic systems are affected in Parkinson's disease. These factors may be at the basis of specific facets of PD-MCI for which dopaminergic involvement has not been conclusive. Finally, the impact of both dopaminergic and noradrenergic deficiency on motivational states in Parkinson's disease is examined in light of a plausible link between apathy and cognitive deficits. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Anstis S.,University of California at San Diego | Vergeer M.,Brain Mind Institute | Van Lier R.,Radboud University Nijmegen
Journal of Vision | Year: 2012

It has long been known that colored images may elicit afterimages in complementary colors. We have already shown (Van Lier, Vergeer, & Anstis, 2009) that one and the same adapting image may result in different afterimage colors, depending on the test contours presented after the colored image. The color of the afterimage depends on two adapting colors, those both inside and outside the test. Here, we further explore this phenomenon and show that the color-contour interactions shown for afterimage colors also occur for "real"colors. We argue that similar mechanisms apply for both types of stimulation. © 2012 ARVO. Source

Tsika E.,Brain Mind Institute | Moore D.J.,Brain Mind Institute
Current Neurology and Neuroscience Reports | Year: 2012

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of familial Parkinson's disease (PD), whereas common variation at the LRRK2 locus is associated with an increased risk of idiopathic PD. Considerable progress has been made toward understanding the biological functions of LRRK2 and the molecular mechanisms underlying the pathogenic effects of disease-associated mutations. The development of neuronal culture models and transgenic or viral-based rodent models have proved useful for identifying a number of emerging pathways implicated in LRRK2-dependent neuronal damage, including the microtubule network, actin cytoskeleton, autophagy, mitochondria, vesicular trafficking, and protein quality control. However, many important questions remain to be posed and answered. Elucidating the molecular mechanisms and pathways underlying LRRK2-mediated neurodegeneration is critical for the identification of new molecular targets for therapeutic intervention in PD. In this review we discuss recent advances and unanswered questions in understanding the pathophysiology of LRRK2. © Springer Science+Business Media, LLC 2012. Source

Discover hidden collaborations