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PL05-03
THE NEUROANATOMY OF CTE
Dara Dickstein
Icahn School of Medicine at Mount Sinai, Neuroscience, New York,
USA
Chronic traumatic encephalopathy (CTE) is a neurodegenerative
disorder associated with repetitive head trauma. Most instances of
CTE occur as a result of mild traumatic brain injuries (TBI) in athlete
populations. Recently, CTE has also been associated with blast-in-
duced injuries in military personnel and other forms of neurotrauma.
Pathologically, CTE is characterized by the deposition of hyperpho-
sphorylated tau (p-tau) protein in neurofibrillary tangles, astrocytic
tangles, and neurites in the neocortex and the superficial layers of the
medial temporal lobe, diencephalon, and brainstem. The definitive
diagnosis of CTE can only be determined at autopsy. However, recent
advancements in magnetic resonance imaging (MRI) and positron
emission tomography (PET) have significantly aided in the diagnosis
of CTE and are crucial in distinguishing CTE from other forms of
neurodegeneration, such as Alzheimer’s disease. PET tracers for
biomarkers such as p-tau and inflammation are in early experimental
stages and are currently being used to help confirm the diagnosis of
CTE in living research participants. We have recently used such
modalities to diagnose and distinguish CTE from AD in an NFL
player with a history multiple concussions, and in a patient with
frontotemporal dementia and a single, severe TBI. It is apparent that
in vivo
biomarkers and neuroimaging techniques hold promise for
developing an
in vivo
diagnostic technique for CTE and could help
identify preventative and therapeutic targets.
Keywords: Chronic traumatic brain injury, phosphorylated tau,
magnetic resonance imaging (MRI), positron emission tomography
(PET, Alzheimer’s disease
PL06 Cell Death Is Still Alive
PL06-01
AUTOPHAGY AND NEURODEGENERATION
Esperanza Arias
Albert Einstein College of Medicine - Bronx, NY., Developmental and
Molecular Biology Dept & Institute for Aging Studies, Bronx, USA
Autophagy is a conserved lysosomal degradative process to recycle
and eliminate damaged or unused cellular components, including or-
ganelles, protein aggregates and lipids. These substrates reach lyso-
somes by several distinct mechanisms, including selective
translocation across the lysosomal membrane known as Chaperone-
mediated autophagy (CMA). This cellular process is essential for
neuronal homeostasis, and its dysfunction has been directly linked to a
growing number of neurodegenerative disorders. Autophagy has been
shown to be affected at different steps depending on the neurode-
generative disorder. A proper characterization of the molecular
players affected in the autophagic process in the different disorders
could be key to determine rate of progress of the pathologies and will
be essential for developing targeted therapeutic approaches for each
disease based on modulation of autophagy. In this talk, I will provide
an overview of the role of autophagy in neurodegenerative diseases,
with particular focus on selective forms of autophagy and discuss
possible novel future therapeutic approaches based on the repair of the
lysosomal system in the affected neurons.
Keywords: Autophagy, Chaperone-mediated autophagy
PL06-02
HEAVY METAL KILLS: ZINC IS AN ENDOGENOUS SUP-
PRESSOR OF CELL SURVIVAL AND AXON REGENERA-
TION AFTER OPTIC NERVE INJURY
Larry Benowitz
1
, Yiqing Li
1
, Stephen Lippard
2
, Paul Rosenberg
3
1
Boston Children’s Hospital/Harvard Medical School, Neurosurgery,
Boston, USA
2
MIT, Chemistry, Cambridge, MA
3
Boston Children’s Hospital/Harvard Medical School, Neurology,
Boston, USA
Like other CNS pathways, the optic nerve cannot regenerate if injured,
causing lifelong losses in vision. We recently showed that retinal gan-
glion cells (RGCs), the projection neurons of the eye, can be induced to
regenerate damaged axons back to the brain by combining intraocular
inflammation (to elevate levels of the growth factor oncomodulin), a
cAMP analog, and
pten
gene deletion. Under these conditions, some
RGCs reconnect to appropriate target areas in the brain and restore simple
visual responses. However, most RGCs continue to die and only 10% of
surviving RGCs regenerate their axons. Because Zn
2
+
has been impli-
cated in cell death in other systems, we investigated its possible role here.
Both autometallography and the fluorescent zinc sensor Zinpyr-1 re-
vealed a dramatic increase in free Zn
2
+
in amacrine cell synapses onto
RGC dendrites within hours of nerve injury and a delayed transfer to
RGCs themselves. Presynaptic Zn
2
+
accumulation requires nitric oxide
production via NOS1 and the vesicular zinc transporter protein ZnT3.
Chelating Zn
2
+
using TPEN or ZX1, or deleting the gene for ZnT3
(
slc30a3
), reduces Zn
2
+
in amacrine cell terminals and within RGCs and
leads to enduring RGC survival. Unexpectedly, these treatments also
induce extensive axon regeneration. Thus, Zn
2
+
is a major suppressor of
optic nerve regeneration. It will be important to investigate whether Zn
2
+
chelators also promote regeneration after other types of CNS injury.
Keywords: zinc, retina, optic nerve, synaptic, axon regeneration,
retrograde signaling
PL06-03
TARGETING THE HOMEOSTATIC ARM OF THE ER
STRESS PATHWAY IMPROVES FUNCTIONAL RECOVERY
AFTER SCI
Sujata Saraswat
, Ashley Mullins, Michal Hetman, Scott Whittemore
University of Louisville, Neurological Surgery, LOUISVILLE, USA
Activation of the endoplasmic reticulum (ER) stress response (ERSR)
is involved in the pathogenesis of numerous CNS myelin abnormal-
ities, yet its role in traumatic spinal cord injury (SCI)-induced de-
myelination is not known. ERSR is activated to maintain protein
homeostasis in the ER in response to distinct cellular insults including
hypoxia, ischemia, trauma and oxidative damage. Mammalian ERSR
includes three signal-transduction pathways initiated by ER stress-
sensing proteins: protein kinase RNA-like ER kinase (PERK), inosi-
tol-requiring protein-1 (IRE1), and activating transcription factor-6
(ATF6). PERK activation leads to the phosphorylation of the eu-
karyotic initiation factor 2
a
(eIF2
a
) and selective translation of ATF4
and CCAAT/enhancer binding homologous protein (CHOP). Re-
cently, we showed significant improvement in hindlimb locomotion in
CHOP
-/-
mice with thoracic contusive SCI. Parallel pharmacological
studies using salubrinal (a selective inhibitor of cellular complexes
that dephosphorylate eukaryotic translation initiation factor 2 subunit
a
) demonstrated a significant improvement in locomotion using basso
mouse scale scores. Gait analysis showed significant increase in
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