Book of abstracts - British Neuroscience Association

47.03
VAP proteins
Skehel P
Center for Neuroscience Research,, University of Edinburgh,,
Edinburgh., EH8 9JZ,
VAP proteins are intracellular membrane proteins enriched on the
cytoplasmic surface of the endoplasmic reticulum. They have been
shown to mediate interactions between the ER and both cytosolic and
cytoskeletal factors, and are implicated in membrane trafficking
events. The proteins contain three structural features: an N-terminal
domain homologous to the nematode Major Sperm Protein (MSP), a
central coiled coil region, and a hydrophobic C-terminal membrane
anchoring domain. Recently a mis-sense mutation in the vapb gene
was found to be linked to a familial form of motor neuron disease
classified as Amyotrophic Lateral Sclerosis type 8 (ALS8). The
mutation results in the substitution of a proline by a serine residue
within a highly conserved region of the MSP domain. When expressed
in cultured cells this structural change causes the protein to form small
intracellular aggregates, containing both the mutant and wild-type
proteins. Recent studies suggest that VAP proteins may perform both
structural and regulatory functions in the homeostatic regulation of
intracellular membrane systems, the mis-function of which may
underlie the degenerative disease ALS8.
47.04
Molecular chaperones as modulators of proteotoxicity in
neurodegenerative disease
Hartl F U
Max-Planck-Institute of Biochemistry, Department of Cellular Biochemistry,
Am Klopferspitz 18, D-82152 Martinsried, Germany;
The formation of insoluble protein aggregates in neurons is a hallmark of
neurodegenerative diseases including those caused by proteins with
expanded polyglutamine (polyQ) repeats (e.g., Huntington’s disease).
However, the mechanistic relationship between polyQ aggregation and its
toxic effects on neurons remains unclear. There are mainly two, nonexclusive,
hypotheses for how polyQ expansions may cause cellular
dysfunction. In one model neurotoxicity results from the ability of polyQexpanded
proteins to recruit other important cellular proteins with short
polyQ stretches into the aggregates. In the other model, aggregating polyQ
proteins cause a partial inhibition of the ubiquitin-proteasome system for
protein degradation. In general, protein misfolding and aggregation are
prevented by the machinery of molecular chaperones. Some chaperones,
such as the members of the Hsp70 family, also modulate polyQ
aggregation and suppress its toxicity. In a recent study, we could show that
the eukaryotic chaperonin TRiC acts synergistically with Hsp70 in this
process. Both chaperone systems appear to form an effective network
preventing the formation of aberrantly folded proteins with cellular toxicity.
Based on these findings, the chaperone pathways involved in de novo
protein folding and protein misfolding may be more similar than anticipated.
48.01
Drosophila as a genetic model for ethanol-induced
neurodegeneration
French R, Heberlein U
. University of California, San Francisco Department of Anatomy, Box
2822, 1550 4th Street, Rock Hall, Room 445, San Francisco, CA
94158.
It is well established that acute, or “binge” ethanol exposure causes
apoptosis of both adult and developing neurons. Further, it is clear that
the response of neurons to an ethanol insult is heavily influenced by
genetic background, but the mechanisms behind this effect are not
well understood. We have found that a single intoxicating exposure to
ethanol causes apoptosis of Drosophila olfactory receptor neurons
(ORNs), accompanied by blackening of the third antennal segment,
which is the primary Drosophila olfactory organ. In addition, we have
shown that shaggy, the Drosophila homolog of glycogen synthase
kinase 3ƒÒ (GSK-3ƒÒ), is required for ethanol-induced apoptosis.
GSK-3ƒÒ has previously been implicated in the mediation of cell
death under a wide variety of neurotoxic conditions, but its targets in
response to ethanol insult are not known. Finally, we have
demonstrated that the GSK-3 inhibitor lithium is protective against the
neurotoxic effects of ethanol, indicating the possibility for
pharmacological intervention in cases of alcohol-induced
neurodegeneration. The system we describe will allow us to
investigate the genetic and molecular basis of ethanol-induced
apoptosis in general, and specifically to identify targets of GSK-3ƒÒ in
programmed cell death.
48.02
Measuring motivation for moonshine in mutant mice; altered
responses to booze and drugs in mice with mutations of GABAA
receptor alpha subunits
Stephens D N
Psychology, University of Sussex, Brighton, BN1 9QG
A primary action of alcohol is facilitation of transmission at GABAA
receptors, pentameric structures, consisting of a,b, g subunits. Each
subunit occurs in several isoforms. We investigated the consequences of
deleting two a isoforms, a2 and a5, on behavioural effects of alcohol and
cocaine. a5 knockout mice consumed less ethanol at concentrations above
10%, but did not differ from wildtypes in performing an operant response to
obtain ethanol/sucrose mixtures. A novel benzodiazepine receptor ligand,
L-792782 (0.03 – 3 mg/kg) with inverse agonist activity selective for a5-
containing GABAA receptors, decreased lever-pressing rates for 10%
ethanol at doses giving rise to 90% receptor occupancy, but did not affect
lever-pressing for 4% sucrose. Furthermore, the non-selective inverse
agonist, R015-4513, which reduced lever-pressing for ethanol/sucrose in
wildtype mice, had less effect in a5 knockouts; lever-pressing for sucrose
was unaffected. Thus, although a5 subunits are not essential to signaling
ethanol reward, inverse agonists acting at a5-containing receptors can
reduce ethanol self-administration. Genetic variants of the GABAA receptor
a2 subunit gene (GABRA2) have been associated with human alcohol
dependence. At ethanol concentrations above 10%, a2 knockout mice
consumed more alcohol, and showed a greater preference for alcohol than
wildtype mice. However, there were no effects of the deletion on rates of
lever pressing (motivation) to obtain ethanol. Thus, although both a2 and
a5-containing GABAA receptors influence measures relevant to alcohol
abuse, their precise role in mediating alcohol reward remains unclear.
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