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.
