Book of abstracts - British Neuroscience Association

57.17
An analysis of DJ-1 (PARK7) and tau isoform expression in
neurodegenerative disorders
Bandopadhyay R, Kumaran R, Kingsbury A, de Silva R, Mann D,
Holton J, Revesz T, Lees A
Reta Lila Weston Institute, Institute of Neurology, UCL, 1 Wakefield
Street, WC1N 1PJ
Homozygous mutations in the DJ-1 gene are associated with
autosomal recessive PD but its link to disease pathogenesis is
unknown. This study examines DJ-1 expression in a variety of
neurodegenerative disorders, AD, Pick’s (PiD), PSP, CBD, FTLD-with
tau mutations in which hyperphosphorylated-tau deposits are a major
pathological signature, and its co-existence with the two major
isoforms of tau, namely 3R and 4R tau by immunohistochemistry and
double confocal fluorescence microscopy. DJ-1 immunoreactivity (DJ-
1-IR) was present in neurofibrillary tangles (NFTs), neuropil threads
(NTs), and extracelluar plaques in AD. Tau inclusions in AD are
composed of 3R and 4R tau. DJ-1 -IR was present in a subset of Pick
bodies which are 3R tau positive. In PSP, a few DJ-1 positive NFT’s,
NTs and glial inclusions were present in all cases examined.
Interestingly, in cases of FTLD with tau mutations that are 3R tau
negative, DJ-1 was present mostly in glial inclusions. The FTLD-
R406W tau mutation cases which are both 3R and 4R tau positive,
DJ-1 IR was associated mainly with NFTs and NTs. Thus DJ-1 is
associated with both 3R and 4R tau-isoform inclusions and in both
neuronal and glial inclusions. Furthermore, DJ-1 is enriched in
sarkosyl-insoluble fractions in AD and PiD brains, which also contain
hyperphosphorylated tau. DJ-1-IR was not associated with ubiquitin
inclusions in FTLD-U cases. DJ-1 deposition in tau inclusions is likely
to be a specific phenomenon and may contribute to disease
pathogenesis.
57.18
Lower brain stem neurons in Parkinson’s disease
Kingsbury A, Hussein K, Bandopadhyay R, Lees A
Reta Lila Weston Institute, Institute of Neurology, UCL, 1 Wakefield Street
WC1N 1PJ
It is well-established that deposition of the pre-synaptic protein alpha
synuclein in neuronal perikarya and processes is a major component of
pathological change in Parkinsons’s disease (PD), although its precise role
in the disease process is unclear. A recent model of progression of PD
pathology proposes that alpha synuclein deposition begins in the lower
brain stem before the motor systems are affected and the clinical signs of
the disease appear. It has also been proposed that alpha synuclein
deposition in neurons and processes may reflect altered axonal transport in
affected nuclei. We report here preliminary findings on the involvement of
lower brain stem neurons in PD. Twelve neuropathologically-evaluated
sporadic PD cases, with nigral neurodegeneration and Lewy body
formation in nigra and cortex were studied. All cases had alpha synuclein
deposition in brain stem neurons and neuronal processes, as predicted by
the model, varying between light and intense. Protein markers of axonal
transport, kinesin and dynein, were examined in lower brain stem by
immunohistochemistry and immunoblotting. Both proteins were expressed
in lower brain stem neurons, including cranial nerve nuclei, inferior olive,
neurons of the central nucleus of the medulla and neuronal processes.
Dynein appeared to stain processes more strongly than kinesin.
Immunoblotting showed that levels of expression of kinesin and dynein
extracted from lower brain stem were unaffected by the disease and
subjective assessment of the immunochemical findings indicated that the
expression of both proteins was similar in PD cases and controls.
57.19
The relationship between oxidative DNA damage and somatic
mutations in Alzheimer’s disease
Timms S C, Nagy Z
Division of Neuroscience, Medical School, University of Birmingham,
B15 2TT
The cell cycle hypothesis for the pathogenesis of Alzheimer’s disease
(AD) postulates that the disease-related pathology is due to aberrant
cell-cycle re-entry of neurones followed by a regulatory failure at the
G1/S transition point. There is direct evidence that neuronal DNA
replication precedes the development of Alzheimer-type pathology.
Although many hypotheses have been formulated, the causes of this
cell cycle deregulation and subsequent neuronal damage are still
elusive. Oxidative stress is one of the factors thought to contribute to
cellular dysfunction and death following cell cycle activation.
We investigated the hypothesis that oxidative stress might contribute
to the accumulation of somatic mutations (genomic instability) in
neurones which, if left unrepaired, could further hinder the functional
integrity of these cells.
In order to investigate genomic instability we carried out comparative
RAPD analysis from two different parts of the brain in AD patients and
controls. 8-hydroxi guanesin, a marker of oxidative DNA damage, was
quantified by ELISA. The expression of neuronal markers, Map-2 and
synaptophysin, were also quantified by ELISA.
Results showed significant decreases in overall neuronal and synaptic
densities in AD brains compared to controls. There was a significant
positive correlation between genomic instability and oxidative stress.
However, there was no significant difference in oxidative damage (8-
HG) per neurone or genomic instability between AD brains and
controls.
Our data indicate that while oxidative DNA damage might contribute to
neuronal dysfunction and loss in AD, the process is not necessarily
disease-specific.
57.20
Neurotoxicity due to overexpression of drosophila tau is comparable
to that seen with human tau
Ubhi K, Shaibah H, Newman T, Shepherd D, Mudher A
School Of Biological Sciences, University Of Southampton, Bassett
Crescent East, Southampton, SO16 7PX
Neurofibrillary tangles containing the microtubule-associated protein tau,
together with extracellular amyloid plaques comprise the two characteristic
neuropathological features of Alzheimer’s disease. Tau in these tangles is
abnormal in a number of aspects including phosphorylation status and
structure; similar abnormalities are also associated with a group of
disorders collectively known as tauopathies.
To model these disorders, human tau has been overexpressed in neuronal
populations in Drosophila melanogaster resulting in neuronal degeneration,
diminished locomotor activity, disrupted axonal transport and impaired
synaptic function. These effects are seen prior to neuronal death and in the
absence of tangle formation.
Although the Drosophila tau protein shares a large degree of homology with
human tau, is unknown how the effects of overexpression of human tau in
Drosophila compare to overexpression of Drosophila tau.
Drosophila tau was overexpressed in larval motorneurones to compare its
effects with that of human tau. The locomotor abilities and axonal transport
characteristics of these larvae were assessed as previously described
(Mudher et al 2004)
Overexpression of Drosophila tau led to a similar decrease in locomotor
activity as seen with overexpression of human 3RT. The effects of
overexpression of Drosophila tau on axonal transport were also
investigated. These results show that overexpression of Drosophila tau
leads to neurotoxicity that is comparable to that seen with overexpression
of human tau. This indicates that it is overexpression of tau per se that is
detrimental to neuronal function and that neuronal degeneration is not a
feature of the specific overexpression of human tau in these models.
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