NNS 2015 Program & Abstract Book

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

, Yiqing Li

, Stephen Lippard

, Paul Rosenberg

Boston Children’s Hospital/Harvard Medical School, Neurosurgery,

Boston, USA

MIT, Chemistry, Cambridge, MA

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

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

in amacrine cell synapses onto

RGC dendrites within hours of nerve injury and a delayed transfer to

RGCs themselves. Presynaptic Zn

accumulation requires nitric oxide

production via NOS1 and the vesicular zinc transporter protein ZnT3.

Chelating Zn

using TPEN or ZX1, or deleting the gene for ZnT3

(

slc30a3

), reduces Zn

in amacrine cell terminals and within RGCs and

leads to enduring RGC survival. Unexpectedly, these treatments also

induce extensive axon regeneration. Thus, Zn

is a major suppressor of

optic nerve regeneration. It will be important to investigate whether Zn

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

(eIF2

) 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

) demonstrated a significant improvement in locomotion using basso

mouse scale scores. Gait analysis showed significant increase in

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