Colloque Medecine et Recherche of La Fondation Ipsen: 'Intracellular Traffic and Neurodegenerative Disorders'.

PARIS -- The 23rd Colloque Medecine et Recherche of La Fondation Ipsen dedicated to the Alzheimer series was held in Paris on 28 April 2008. Entitled "Intracellular Traffic and Neurodegenerative Disorders" this meeting gathered fourteen leading researchers focused on the intracellular world. The participants presented their most recent findings about the disturbances that may lead to neurodegeneration, including how underlying disturbances contribute to the malfunctioning of cells, what the consequences of a dysfunctional key molecule are for the surrounding networks and the possible ways to correct these diruptions. These initial glimpses into the enormous complexity and subtlety of protein processing and targeting within cells are beginning to reveal how the possible pathways leading to neurodegeneration are numerous and varied. New possibilities for effective prevention or treatment of these devastating diseases were presented at this colloque.

The inside of each cell is a very busy place - a microscopic world of molecules that work together, interacting in groups, sequences or networks. Much as in the macroscopic world, a disturbance caused for instance by a rogue molecule can have far-reaching, sometimes catastrophic effects on the harmony and balance in the interactions. For many years, much attention has been paid to rogue proteins that seem to be the cause of neuron dysfunction and death, such as amyloid beta and tau in Alzheimer disease.

Neurons have a particular problem with intracellular communication because the elongated axon and dendrites place many synapses a long way from the nucleus. Special mechanisms are required for communicating the molecular requirements of the synapses to the nucleus, and for directing the proteins synthesized in the cell body in response to these signals to the synapses that need them, particularly during synapse formation and the plastic changes associated with learning (Kelsey Martin, Brain Research Institute, UCLA, Los Angeles, USA). This is a complex problem that involves identifying the protein, sorting it into an appropriate pathway and packaging it, with each stage engaging several enzyme-mediated steps. The packaged proteins then have to be transported along the axon or dendrite according to the labels attached to them, each process again involving complex molecular interactions.

One of the proteins most strongly implicated in the pathology of Alzheimer disease (AD), the tau protein, is a normal part of the axonal transport mechanism (Eva-Maria Mandelkow, Max-Planck Unit for Structural Molecular Biology, DESY, Hamburg, Germany). The other, the amyloid precursor protein (APP) is a molecule that is packaged and delivered from the cell body to synapses, which is being cut up by cleavage enzymes into its active components on the way (Konrad Beyreuther, Universitat Heidelberg, Heidelberg, Germany; Christian Haass, Ludwig-Maximilians University, Munich, Germany). Mutations in the genes coding for tau and APP are well known to disrupt these normal processes, resulting in pathogenic forms of the molecules. Mutations in a protein, presenilin, that forms part of one of the APP cleavage enzymes also interferes with normal APP processing. However, these mutations, which all lead to a build up of the plaques and tangles characteristic of AD, account for only a small proportion of cases of AD. No clear cause of the more common, so-called sporadic form of the disease has been found. Looking more closely at the molecular networks surrounding these molecules, and around similar 'rogue' molecules implicated in other neurodegenerative diseases, may provide more clues to pathogenesis and lead to new pharmaceutical therapies.

Axonal transport

Proteins move along axons as if along railway tracks, which are provided by elongated structures known as microtubules. They are driven along the tracks by the molecular motor proteins kinesin and dynein, assisted by ancillary proteins such as tau. Abnormalities in the tau protein cause it to aggregate in an insoluble form, disrupting the transport process by preventing the motor proteins access to the microtubules. The result is that the terminals become depleted not only of a supply of freshly made proteins but also of mitochondria, which leads to energy depletion and the disintegration of synapses (Mandelkow). Among the molecules transported from the cell body to the terminals is APP, encapsulated in vesicles which are attached to kinesin (Beyreuther).

In the opposite, or retrograde, direction, proteins from the terminals returning along the axon to the cell body include worn-out molecules going to be broken down and recycled, and signal molecules such as growth factors. They are carried along the microtubules by dynein, which requires another molecule, dynactin, to activate it. Mutations in dynactin are associated with the degeneration of motor neurons, some of which have particularly long axons. Another molecule implicated in motor neuron degeneration when mutated, SOD1, assists in regulating the efficiency of the retrograde traffic (Erika Holzbaur, University of Pennsylvania School of Medicine, Philadelphia, USA). In Huntington disease, the mutated protein huntingtin prevents the retrograde transport of an essential growth factor, BDNF (Brain-derived neurotrophic factor), in striatal neurons, resulting in the deaths of their synaptic terminals (Frederic Saudou, UMR 146 CNRS, Institut Curie, Orsay, France).

Chaperones, molecules that assist protein folding and packaging, also seem to be important for healthy axonal transport. Failure of axonal transport is beginning to be seen as a central feature of neurodegenerative diseases, and further study of the pathophysiological mechanisms involved should lead to a better understanding of the causes of neurodegeneration, and new methods of treatment (William Mobley, Stanford University School of Medicine, Stanford, USA).

APP sorting and cleavage

APP, synthesized in the cell body, is destined for insertion into plasma membranes. Molecules of this type are sorted in the endoplasmic reticulum according to particular sequences of amino acids on the tail of the protein, which are recognized by a complex of proteins termed a retromer (Matthew Seaman, Addenbrooks Hospital, Cambridge, UK). Once inserted in the membrane, the APP molecule can be cleaved in one of two ways: by a-secretase, releasing the harmless sAPP; or by the b- and g-secretases, which produces the amyloid- beta (Ab) fragment that accumulates to form the characteristic plaques found in AD. Which path is chosen partly depends on the combination of the retromer with a sorting protein known as SORLA (Seaman), which directs APP towards the alpha-secretase pathway (Thomas Willnow, Max Delbruck Center for Molecular Medicine, Berlin, Germany). Patients with AD have a higher incidence of a particular variant of the gene coding for SORLA, which seems to reduce its efficiency, so increasing the amount of APP that is cleaved by the b-/g-secretases to form Ab. But cell biology is never simple - the choice of processing pathway is also regulated by several enzymes that modify the tail of the APP molecule, all of which may be subject to disturbance but are also potential targets for therapeutic regulation of APP processing (Samuel Gandy, Thomas Jefferson University, Philadelphia, USA).

The alpha-secretase cleavage may take place during axonal transport, delivering the processed product to the synaptic terminal, where it may support plasticity and possibly cell-cell recognition (Beyreuther). The g-secretase is an unusual enzyme as it cleaves APP in the part of the molecule that is embedded in the plasma membrane. It is a complex of four proteins, one being presenilin, mutations that lead to an increase in Ab production. Comparison with similar enzymes is providing some clues to how it works (Haass).

A common feature of neurodegenerative diseases is that significant proteins, such as tau and APP, become mis-folded and so form problematic aggregates. Work in a yeast model is showing how mis-folded proteins associated with the pathology of Parkinson disease and Huntington disease affect the traffic of molecules between different compartments in the cell body or along axons. In Huntington disease, the network of other proteins that supports this trafficking may include the prion protein (Susan Lindquist, Whitehead Institute, Cambridge, USA). Another surprise is that the protein ubiquitin, long known as a label for molecules destined for destruction, is also an important regulator of protein traffic and turnover, particularly of neurotransmitter receptors, channels and transporter molecules that are embedded in cell membranes. Disturbing this mechanism may also be a precursor to neurodegeneration (Alexander Sorkin, University of Colorado, Aurora, USA).

The meeting has been organized by Peter St George Hyslop (University of Toronto, Toronto, Canada), William Mobley (Stanford University School of Medicine, Stanford, USA) and Yves Christen (Fondation IPSEN, Paris).

La Fondation Ipsen

Established in 1983 under the aegis of the Fondation de France, the mission of La Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long-standing action of La Fondation Ipsen is aimed at furthering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialisation of these professions. The ambition of La Fondation Ipsen is not to offer definitive knowledge, but to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Medecine et Recherche, dedicated to six main themes: Alzheimer's disease, neurosciences, longevity, endocrinology, the vascular tree and cancer. In 2007, La Fondation Ipsen started three new series of meetings in partnership with: on the one hand the Salk Institute and Nature magazine focused on Biological Complexity, on the second hand with Nature magazine on Emergence and Convergence, the last series being with Cell magazine and the Massachusetts General Hospital titled Exciting Biologies. Since its beginning, La Fondation Ipsen has organised more than 90 international conferences, published 65 volumes with renowned publishers and 196 issues of Alzheimer Actualites. It has also awarded dozens of prizes and grants.