Abstract Details

Title Expression of Mutant Human a-synuclein in Oligodendrocytes during Myelination Period Induces Remarkable Glial Inflammation and Demyelination in the Spinal Cord and Brainstem/Cerebellar White Matter: a Novel Model of Multiple System Atrophy-Cerebellar Type and Primary Progressive Multiple Sclerosis

Topic Movement Disorders

Presentation(s) P7 - Poster Session 7 (5:30 PM-6:30 PM)

Poster/Presentation
Number 3-008

Objective To develop a novel model of multiple system atrophy-cerebellar variant (MSA-C) and primary progressive multiple sclerosis (PPMS) by overexpression of mutant humanα-synuclein (α-syn) in oligodendrocytes in a temporarily restrictive manner using Tet-off system.

Background

MSA is classified to parkinsonian (MSA-P) and cerebellar (MSA-C) variants. The hallmark of MSA is α-syn⁺ glial cytoplasmic inclusions in oligodendrocytes. PPMS is supposed to be caused by oligodendrocyte dystrophy while accumulation of α-syn is also seen in MS lesions. There is no established animal models for MSA-C or PPMS.

Design/Methods

We generated and analyzed TetO-α-SynA53T Tg/+; PLP-tTA Tg/+ double transgenic mice (A53Tα-syn mice), which express mutant human A53Tα-syn in oligodendrocytes starting at 8 weeks of age when doxycycline was removed from the feed.

Results A53Tα-syn mice developed progressive mono-, hemi-, and paraparesis and ataxia at 22 weeks of age, culminating in death around 30 weeks. Before the disease onset (at 16 weeks), phosphorylated α-syn focally accumulated in TPPP/25α⁺ oligodendrocytes showing loss of connexin (Cx)47 in the spinal cord and brainstem/cerebellar white matter. Focal demyelination and oligodendrocyte loss started from the phosphorylated α-syn-deposited areas, leading to widespread demyelination. In these lesions, increased GFAP⁺ astrocytes showed extensive loss of Cx43/Cx30, phagocytizing aggregated α-syn. Numerous arginase-1⁺ microglia were highly activated, surrounding deposited phosphorylated α-syn. Gene ontology analysis using mciroarray data of the spinal cord revealed that dysregulation differentially expressed genes were significantly enriched in immune system, and innate immune and inflammatory responses. Re-feeding of doxycycline at 23 weeks but not at 27 weeks recovered the neurological deficits and pathological abnormalities.

Conclusions

Our findings suggest that expression of mutant α-syn in oligodendrocytes during myelination period induces remarkable glial inflammation and demyelination in the spinal cord and brainstem/cerebellar white matter, resembling MSA-C and partialy PPMS.

Authors/Disclosures
Katsuhisa Masaki, MD (Kyushu university) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ryo Yamasaki	No disclosure on file
	No disclosure on file
Jun-ichi Kira, MD, PhD (Kyushu University)	Dr. Kira has nothing to disclose.

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Abstract Details