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Viruses and Neurological DiseaseViruses and Neurological Disease

Richard Jay Smeyne, Ph.D.Richard Jay Smeyne, Ph.D.

Department ofDepartment of Developmental NeurobiologyDevelopmental Neurobiology

St. Jude Childrens Research HospitalSt. Jude Childrens Research Hospital

Alzforum Webinar

Feb 24, 2011

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PD associated viruses

Influenza, Herpes simplex, Coxsackie,

Japanese encephalitis, HIV virus

Neuropsychiatric disorders seen withflu pandemics

1510, 1890, 1918(H1N1),

1958(H3N2), 1997(H5N1), 2009(H1N1)-

Neurological symptoms seen also with

H5N1

Poultry, ferrets, mice

domestic cats and dogs

Humans

Courtesy of Robert Webster,

filmed by David Boltz, Ph.D.,

Lao, 2008

Viruses have been associated with

neurological disorders

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Viral Hypothesis of PD

500 million peoples were

infected with H1N1

Spanish flu

20-40 million (4~8%) died

of acute influenza

1918-1926

15 million people

developed encephalitis

5 million dead

1900 1918 1926 1930 1960

5 million who survived from

encephalitis later developed

Post encephalitis

parkinsonism

??

High fever, headache, double vision,

somnolence, upper body weakness,

tremors, neck rigidity, behavioral

changes

Early onset and rapid progression

Bilateral diffuse degeneration and gliosis of SN and LC

Absence of Lewy bodies

Widespread presence of neurofibrillary tangles

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Neuron and Microglia cell are infected by H5N1

influenza virus

ca b

G :-III tubulin

R : anti-NPG : Iba-1

R : anti-NP

G : GFAP

R : anti-NP

d

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Olf. BurbOlf. Burb

Mitral cellMitral cell

OlfactoryOlfactory

nu.nu.

Piri. Ctx.Piri. Ctx.

LCLCThalamusThalamus

AmygdalaAmygdala

Nose orNose or

TongueTongue

Pontine Nu.Pontine Nu.

Sol. Nu.

Lung orG.I.

CerebralCerebral

ctx.ctx.

SNSN

Nu. X

Cau.pu.Cau.pu.

Nu.Nu.

Nu. VII

Spinal cord

Progression of infection in the nervous system

SN

Tyrosine hydroxylase

Viral NP

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midbrain

cerebellum

Activated caspseActivated caspse--3 expression is seen in the3 expression is seen in the

brain following infection with H5N1.brain following infection with H5N1.

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H5N1 infection results in alphaH5N1 infection results in alpha--synucleinsynuclein

pathologypathology

SN, Control

Human PDHuman PD Human PD, No primaryHuman PD, No primaryHuman PDHuman PD

SN, Dpi60 Hippo. Dpi 60

R: anti-NP G: Tyrosine hydroxylase, B: DAPI

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Normalized % density of the pSer129 synuclein

protein

Proteinase-K treated brains

(Insoluble phosphorylated synuclein level)

Structure control H5N1 Statistics

Olfactory bulb 100 19 189 23 P 0.01

Hippocampus 100 21 244 25 P 0.001

Locus coeruleus 100 7 168 10 P 0.001

Solitary nucleus 100 7 163 8 P 0.001

Lower brainstem 100 21 135 14 n.s.

Cerebellum 100 16 108 12 n.s.

Affected

by H5N1

a

b

Control, OBControl, OB

H5N1, OBH5N1, OB

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