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The APCs of Nerve Cell Function
Summary
Best known for its role in colorectal cancer, the protein
adenomatous polyposis coli (APC) has recently been found
to play an essential role in the nervous system. This new
study provides novel insights into the molecular basis
of neurological disorders such as Alzheimer’s disease,
mental retardation, schizophrenia, and autism spectrum
disorders.
BOSTON (June, 16 2008) — Rapid information processing
in the nervous system requires synapses, specialized contact
sites between nerve cells and their targets. One particular
synapse type, cholinergic, uses the chemical transmitter
acetylcholine to communicate between nerve cells. Cholinergic
synapses are essential for normal learning and memory, arousal,
attention, and all autonomic (involuntary) nervous system
functions. Malfunction of cholinergic synapses is implicated
in Alzheimer’s disease, age-related hearing loss, autonomic
neuropathies, and certain forms of epilepsy and schizophrenia.
Despite the importance of cholinergic synapses for cognitive
and autonomic functions, little is known about the mechanisms
that direct their assembly during development. In a new study
published in the June 2008 issue of Molecular and Cellular
Neuroscience, researchers at Tufts University School
of Medicine (TUSM), uncover mechanisms that direct cholinergic
synapse assembly between neurons in vivo.
“We have identified the protein adenomatous polyposis
coli (APC) as a key organizer of a multi-protein complex
that is required for assembly of neuronal cholinergic synapses,” says
corresponding author Michele H. Jacob, PhD, professor of
neuroscience at TUSM and member of the neuroscience program
faculty of the Sackler School of Graduate Biomedical Sciences. “APC
is expressed in all cell types and has multiple functions
and binding partners. It is best known for its role in colorectal
cancer. Our work defines a novel role for APC in neurons.
We show that APC brings together several proteins at the
synapse and coordinates their functions in directing the
surface membrane delivery and stable retention of nicotinic
acetylcholine receptors at the synapse.”
“A single nerve cell synthesizes multiple different
neurotransmitter receptor types. The nerve cell must target
each of them to distinct synaptic sites that oppose incoming
nerve cell contacts that release the correct transmitter
to activate that receptor type. Matching of receptor and
transmitter types is critical for proper function,” states
Madelaine Rosenberg, PhD, first author and research associate
in the department of neuroscience at TUSM. Rosenberg says
that APC and its associated proteins play a key role in accomplishing
this task at cholinergic synapses. The authors report that
APC interacts with and positions the microtubule plus-end
binding protein EB1 and thereby directs the delivery of acetylcholine
receptors to restricted surface membrane regions. APC and
EB1 interact with other proteins, cytoskeletal regulators
and adapter proteins, which together stabilize the scaffold
at the synapse and link acetylcholine receptors to APC at
the complex. This study identifies several novel components
of neuronal nicotinic cholinergic synapses.
Jacob and colleagues showed that blocking APC function led
to dramatic and specific decreases in acetylcholine receptor
levels at synapses. They showed this by using molecular techniques
to manipulate APC protein interactions during synapse formation. “We
study an in vivo model system to gain insights into
mechanisms that likely direct synapse assembly and function
in the human nervous system,” Jacob explains. She further
suggests that their data “support the emerging concept
that APC is a central organizer of a core multi-protein complex
that directs the assembly of excitatory, but not inhibitory,
synapses in the vertebrate nervous system. The importance
of APC’s neural role is highlighted by reports that
loss of function gene mutations correlate with mental retardation,
schizophrenia, and autism spectrum disorders.” Jacob
notes, “By identifying the synapse organizing role
of APC and its associated proteins, our findings bring us
closer to understanding disorders of cognition and neurological
function on a molecular level.”
This study is funded by the National Institute of Neurological
Disorders and Stroke (NINDS) through grants to Dr. Jacob
and the Tufts Center for Neuroscience Research, and the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
through Tufts Medical Center Digestive Disease Center. Both
NINDS and NIDDK are part of the National Institutes of Health.
Rosenberg MM, Yang F, Giovanni M, Mohn J, Temburni MK, Jacob
M. Molecular and Cellular Neuroscience. 2008 (June);38(2):138-152.“Adenomatous
polyposis coli plays a key role, in vivo, in coordinating
assembly of the neuronal nicotinic postsynaptic complex.” Published
online March 4, 2008, doi:10.1016/j.mcn.2008.02.006
If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586. |
