Colloque Médecine et Recherche of La Fondation Ipsen: "Intracellular Traffic and Neurodegenerative Disorders"

The 23rd Colloque Médecine 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

Universität 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 "Ëœrogue´ 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 (Frédéric

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 α-secretase, releasing the harmless

sAPP; or by the or by the β- and γ-secretases, which produces the amyloid- beta (Aβ)

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 β-/γ-secretases to form Aβ, 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 α-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 Aβ 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 Médecine 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 Actualités.

It has also awarded dozens of prizes and grants.