close

Вход

Забыли?

вход по аккаунту

?

Derek Denny-Brown Plenary Sessions (1Ц7).

код для вставкиСкачать
132nd Annual Meeting
Tuesday, October 9, 2007
Derek Denny-Brown
New Member Symposium
Abstracts
pairment, suggesting that LR11 may be a biomarker for disease progression. Finally, in basal forebrain of AD patients,
we found an association between LR11 and tangle-bearing
neurons, linking LR11 with tau-based neuropathology. The
rapidly growing body of evidence suggests that LR11 represents an important mediator of AD pathogenesis. Study supported by NIH-NIA (R01AG24214, P50AG025688,
P01AG14449, F31NS055881), Institute for the Study of
Aging, American Health Assistance Foundation, Luttrell
Foundation.
(8:00-8:25 AM)
1. Functional Characterization of a Family of Proteins
Related to the SPG3A Protein Atlastin
Craig D. Blackstone, MD, PhD,
National Institute of Neurological Disorders and Stroke,
Bethesda, MD
Mutations in atlastin-1, an oligomeric GTPase localized to
the cis-Golgi apparatus in brain, are responsible for SPG3A,
an early-onset, autosomal dominant hereditary spastic paraplegia. Previously, we showed that atlastin-1 is also enriched
in axonal growth cones and required for axon outgrowth
during neuronal development (Zhu et al, Hum Molec
Genet, 2006). We have now identified a family of human
atlastin proteins and found that while atlastin-1 is predominantly in brain, atlastin-2 and atlastin-3 are abundant in
other tissues. At the subcellular level, though atlastin-1 is in
cis-Golgi and growth cones, atlastin-2 and atlastin-3 localize
to ER. Knock down of atlastin-2 and atlastin-3 using siRNA
causes Golgi fragmentation in cells, indicating that atlastins
function in ER-to-Golgi trafficking and maintenance of
Golgi structure in addition to axon growth. Interestingly,
though atlastin-1 interacts with the SPG4 protein spastin,
atlastin-2 and atlastin-3 do not, and only atlastin-1 partially
colocalizes with spastin in neuronal processes. Thus, although there may be functional overlap among atlastins in
ER-to-Golgi trafficking, the selectivity of atlastin-1 interactions with spastin may be relevant for pathogenesis of these
two common hereditary spastic paraplegias. Study supported
by Intramural Research Program of the NINDS, National
Institutes of Health.
(8:25-8:50 AM)
2. The Role of LR11/SORL1 in Alzheimer’s Disease
Pathogenesis
James J. Lah, MD, PhD,
Center for Neurodegenerative Disease, Atlanta, GA
Previous studies have implicated LR11 in Alzheimer’s disease
(AD) based on reduced expression in AD, LR11’s ability to
alter amyloid-␤ peptide (A␤) production, and association of
genetic variants of LR11 with AD. Ongoing studies expand
the links between LR11 and AD, and point to LR11 as a
novel target for AD therapeutics. Experiments using LR11deficient mice provide compelling evidence that LR11 can
modulate amyloid pathology. A␤ measurement by ELISA
and immunohistochemistry revealed increases in extracellular
amyloid in hippocampus and cortex of 3-, 4.5-, and
6-month old mice. At 12-months, amyloid accumulation
plateaued in cortex and hippocampus, but LR11-deficient
mice demonstrated increased A␤ deposition in the cerebellum, an area resistant to amyloid pathology. Furthermore,
human studies examining LR11 in controls, individuals with
mild cognitive impairment (MCI), and AD patients demonstrated loss of LR11 in early stages of AD, including MCI.
Significantly, LR11 expression correlated with cognitive im-
(8:50-9:15 AM)
3. Grass Foundation Award in Neuroscience: Deriving
Neural Progenitors from Human Embryonic Stem Cells
for Brain Reparative Therapies
Jack M. Parent, MD, University of Michigan,
Ann Arbor, MI
Human embryonic stem cell (hESC)-derived neural progenitor cell (NPC) transplantation is a promising therapy for
various brain disorders. The optimal NPC differentiation for
grafting is unclear. We examined methods for enriching and
differentiating hESCs into NPC types for transplantation
into a rat stroke model. To enrich for multipotent NPCs,
H7 or H9 hESCs (WiCell) were transfected with hSox3
promoter-GFP or hSox3-Neo-IRES-GFP constructs. Stable
lines were generated using antibiotic selection after transfecting hSox3-GFP-hUbiquitinC-Neo. Neuronal-restricted precursors (NRPs) were identified by polysialylated neural cell
adhesion molecule (PSA-NCAM) immunoreactivity and subjected to fluorescence-activated cell sorting (FACS). NPCs
were transplanted into injured striatum of adult rats 7 d after
stroke. Neural differentiation of hESCs in defined media
yielded nestin/Sox3/ MAP2⫹ NPCs in neural tube-like rosettes. To enrich for multipotent NPCs, hESCs were transfected with Sox3 constructs. Transiently- and stablytransfected hESCs expressed GFP only after neural
differentiation. GFP⫹ cells formed Sox3⫹ rosettes. FACS
for PSA-NCAM⫹ NRPs after 3-week differentiation yielded
over 44%. Many NPCs grafted into intact or infarcted rat
forebrain were detected 1-2 weeks later and expressed nestin,
Sox3 and occasionally b-III-tubulin. Ongoing experiments
are comparing NPC and NRP grafts for integration into
ischemic forebrain. Study supported by NIH (NIGMS)
P20GM069985.
(9:15-9:40 AM)
4. Gene Regulation of Mitochondrial Function in
Diabetic Neuropathy
James W. Russell, MD, University of Maryland,
Baltimore, MD
Mitochondrial degeneration and impaired regulation by coactivator genes is associated with severity of type 2 diabetes,
and potentially with the severity of neurological complications. The normal response to mitochondrial loss is to promote regeneration or fusion. Peroxisome proliferatoractivated receptor-gamma co-activator 1␣ (PGC-1␣),
regulates mitochondrial regeneration and response to oxidative stress. PGC-1␣ stimulates expression of nuclear respiratory factor-1 and -2 (NRF-1 and -2) and mitochondrial transcription factor A (TFAM). In diabetic mice with
neuropathy examined over 6 months there was a reduction
in mitochondrial number and DNA. In response to loss of
mitochondria, PGC1␣ and TFAM mRNAs were upregulated whereas NRF1 and NRF2 were unchanged. Further-
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
S1
more, there was a corresponding reduction in mitofusin 2
(MFN2) expression. MFN2 controls mitochondrial fusion
and is known to be mutated in CMT2. PGC-1␣ knockout
animals develop neuropathy, coupled with loss of mitochondria. In contrast, overexpression of PGC-1␣ in neurons inhibits oxidative injury. In conclusion, diabetic neuropathy is
associated with loss of mitochondria, and changes in gene
regulation of mitochondrial regeneration, oxidative metabolism, and fusion. Therapies that regulate these pathways
would be important in treatment of diabetic neuropathy and
other neurodegenerative disorders associated with oxidative
stress. Study supported in part by NIH NS42056, The Juvenile Diabetes Research Foundation Center for the Study of
Complications in Diabetes (JDRF), Office of Research Development (Medical Research Service), Department of Veterans Affairs.
(10:15-10:40 AM)
5. Modulating Brain Activity to Facilitate Stroke
Recovery
Gottfried Schlaug, MD, PhD, Harvard Medical School,
Boston, MA
Brain imaging and electrophysiological studies have shown
evidence for an increased inhibitory influence of the nonlesional and a reduced inhibitory influence of the lesional
hemisphere. Up-regulating excitability in the lesioned hemisphere (which we tested in the current study), downregulating excitability in the undamaged hemisphere, or a
combination of the two might provide a new therapeutic approach to facilitate recovery. Non-invasive Transcranial Direct Current Stimulation (TDCS) can lead to reversible shifts
in cortical excitability and has the potential to interfere in
these abnormal pathophysiological processes. Chronic stroke
patients with moderate to severe hemiparesis were randomized to receive real-TDCS and simultaneous occupational
therapy (OT) or sham-TDCS and OT for 5 consecutive
days. Each subject underwent 2 fMRI sessions while performing motor tasks and several motor assessments (pre and
post intervention). We found a significant change in the
range of movements of the paretic hand after realTDCS⫹OT which was about 4 times higher than the sham
TDCS-OT change overtime. The real-TDCS⫹OT effects
outlasted the intervention period by at least one week. FMRI
analysis supported the conclusion that cathodal TDCS might
exert its facilitating effect by reducing the transcallosal inhibitory influence of the contralesional, unaffected hemisphere.
Study supported by NIH-RO1-NS045049.
(10:30-10:55 AM)
6. Prospective Evaluation of Pre-symptomatic Infants
with Spinal Muscular Atrophy: Implications for Early
Therapeutic Intervention
Kathryn J. Swoboda, MD, University of Utah,
Salt Lake City, UT
In the most common form of spinal muscular atrophy, SMA
type I, death or severe respiratory insufficiency requiring mechanical ventilation occurred historically in the majority of
infants before 2 years of age. In recent years the increasing
use of proactive nutritional management and non-invasive
respiratory support has resulted in an often considerable ex-
S2
Annals of Neurology
Vol 62 (suppl 11)
2007
tension of lifespan. In 14 infants diagnosed early in the disease course due to a history of an affected sibling, electrophysiologic data (ulnar motor unit number estimation and
maximum compound muscle action potential amplitude)
suggest that distal motor innervation approximates normal
levels at birth. However, progressive and often precipitous
denervation occurs in the pre-symptomatic and early symptomatic phases of the illness. The rate at which this decline
occurs is related to SMA genotype and phenotype. Improved
electrophysiologic outcomes and motor function in a subset
of infants treated prospectively with sodium phenylbutyrate
lends strength to the hypothesis that early intervention in the
neonatal period with therapeutic agents directed to increase
the deficient SMN protein levels could ameliorate disease
progression and severity. If successful, therapeutic intervention in SMA may prove a valuable paradigm for early intervention in other neurodegenerative disorders.
This work was supported by grants from Families of SMA
and MDA. Support for KJS was also provided by a joint
award from the SMA and AAN foundations.
(11:05-11:30 AM)
7. Derek Denny-Brown Neurological Scholar Award:
Neurodegeneration and Regeneration in the Nervous
System
Douglas A. Kerr, MD, PhD, Johns Hopkins University,
Baltimore, MD
We have explored several stem cell-based therapies for refractory neurologic diseases including multiple sclerosis (MS),
transverse myelitis (TM) and spinal muscular atrophy
(SMA). In this talk, I will discuss the status of three of these
projects. In the first, high-dose cyclophosphamide (Revimmune) is explored as a one-time front-loaded therapy to induce long term remission in patients with MS. Revimmune
works by temporarily eliminating maturing and mature immune cells while sparing bone marrow stem cells, thus allowing reconstitution of a naı̈ve immune system without transplantation. As part of a clinical protocol for aggressive MS,
10 patients have been treated with Revimmune and then no
subsequent immunomodulatory therapy for up to 24
months. There was a 90% reduction in gadolinium enhancement by 18 months, a 95% reduction in exacerbation frequency and a 45% reduction in disability.
Preclinical studies in my laboratory focus on the use of
glial restricted precursors (GRPs) as potential therapeutic
agents for CNS demyelinating disorders. Following completion of the preclinical studies, we hope to initiate a single
center, open label pilot study with dose escalation to obtain
preliminary data on the safety and tolerability of GRP cells
in patients with disability from TM.
We recently defined the ability of embryonic stem cellderived motor neurons to functionally replace those destroyed in paralyzed adult rats. This is the first report, to our
knowledge, of the anatomical and functional replacement of
a motor neuron circuit within the adult, mammalian host.
We are currently carrying out large mammal studies to generate the necessary preclinical data and initiate a clinical trial
of ES cell-derived motor neurons to reconstitute motor neurons damaged in infants with the fatal motor neuron disorder SMA.
DOI: 10.1002/ana.11644
Документ
Категория
Без категории
Просмотров
0
Размер файла
52 Кб
Теги
1ц7, plenary, denne, derek, brown, session
1/--страниц
Пожаловаться на содержимое документа