NEWS: Water channel protein implicated in relative of multiple sclerosis

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Public release date: 21-Sep-2005

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American Neurological Association

Water channel protein implicated in relative of multiple sclerosis

San Diego -- Researchers have identified a molecular suspect in a

disorder similar to multiple sclerosis (MS) that attacks the optic

nerve and spinal cord, according to a report presented at the 130th

annual meeting of the American Neurological Association in San Diego.

The protein, called aquaporin-4, is a channel protein that allows

water to move in and out of cells.

" Aquaporin-4 is the first specific molecule to be defined as a target

for the autoimmune response in any form of MS, " said author Vanda A.

Lennon, MD, PhD, of the Mayo Clinic in Rochester, Minnesota. " It is

also the first example of a water channel being the target of any

autoimmune disorder. "

Because there are many other variants of aquaporins throughout the

body, Lennon suggests that these proteins might play a role in poorly

understood autoimmune disorders in other organ systems.

For some time, scientists have understood that multiple sclerosis is

not so much a single disease, but a category of disorders with

similar damage to different parts of the nervous system. Recently,

progress has been made in teasing out a particular syndrome called

neuromyelitis optica (NMO), in which the body mistakenly mounts an

immune attack against the optic nerve and spinal cord.

Last year, Lennon and her colleagues at Mayo, along with

collaborators in Japan, were able to detect a particular antibody

that occurrs in most people with NMO, but not in patients with

" classical " MS.

This is particularly important for clinicians because specific

treatment recommendations to help prevent blindness and other later

symptoms, including paralysis, differ for NMO and MS .

In the present study, Lennon and colleagues have identified an

aquaporin as the target molecule of the NMO antibody. " This finding

is a departure from mainstream thinking about MS and related

disorders, where the major focus of research in the past century has

been the myelin that insulates nerve fibers, and the cell that

manufactures myelin, known as the oligodendrocyte, " said Lennon.

The Mayo Clinic group's work reveals that the protein targeted by the

NMO antibody is not a component of myelin, or of oligodendrocytes.

Aquaporin-4, which is the most abundant water channel in the brain,

is instead located in a different type of cell called astrocytes.

" Aquaporin-4 is concentrated in membranes in the precise site where

spinal cord inflammation is found in NMO patients, " said Lennon.

The next step in this research is to use this knowledge to create an

animal model that can be used to confirm the relationhip between

aquaporin-4 and NMO, as well as to develop new and improved therapies.

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[background/Abstract]

Autoantibody Marker of Neuromyelitis Optica Binds to the Aquaporin-4

Water Channel

Vanda A. Lennon MD, PhD, J. Kryzer, J. Pittock, A.S.

Verkman, R. Hinson, Rochester MN

Water channel proteins, which were the subject of the 2003 Nobel

Prize in Chemistry, have not been implicated in many pathological

disorders, and never in an autoimmune neurological context. Our study

identifies the mercurial-insensitive water channel protein,

aquaporin4 (AQP4), as the disease-specific autoantigen recognized by

an IgG found exclusively in serum of patients with neuromyelitis

optica (NMO; 73% sensitive, >90% specific) and NMO-related disorders

(including relapsing transverse myelitis and optic neuritis).

Traditionally considered a severe variant of multiple sclerosis (MS),

and commonly misdiagnosed (and inappropriately treated) as MS, NMO is

confidently distinguishable from MS when this autoantibody is

detected. AQP4 is the first autoantigen ever identified in the

context of an idiopathic inflammatory demyelinating disorder of the

central nervous system (CNS). Its molecular identification heralds

development of the first authentic animal model for CNS demyelinating

disease, and thence more effective therapies. The most conclusive

experiments, involving the transfection of a non-CNS cell line with

the human AQP4 gene, and the selective precipitation of its expressed

product from cell lysates by IgG in sera of patients with NMO, were

commenced April 7, 2005.

Inflammatory demyelinating diseases of the central nervous system

(CNS) are recognized to be immune-mediated, but no disease-specific

microbial antigen or autoantigen has been identified. Neuromyelitis

optica (NMO) selectively affects optic nerves and spinal cord, and is

considered a severe variant of multiple sclerosis (MS). It is

frequently misdiagnosed as MS, but prognosis and optimal treatments

differ. We recently described an NMO-specific IgG in the serum of 73%

of patients with NMO, and in 58% of patients with Asian optic-spinal

MS. In patients with new onset transverse myelitis or optic neuritis,

seropositivity predicts relapse or future development of NMO.

Patients with classical MS are seronegative. We initially reported

from its immunostaining pattern that NMO-IgG binds to subpial

elements and CNS microvasculature, colocalizing with laminin near the

blood-brain barrier (Lennon, Lancet, 2004). Here we report that,

immunohistochemically, NMOIgG colocalizes precisely with the

aquaporin-4 water channel (AQP4), and does not bind to CNS tissue of

AQP4-null mice. It binds selectively to AQP4-transfected non-CNS

cells, and exclusively immunoprecipitates the AQP4 water channel

component of the dystroglycan protein complex. We conclude that the

autoantigen of NMO-IgG is AQP4 in astrocytic foot processes. NMO may

be the first example of a novel class of autoimmune channelopathy.

http://www.eurekalert.org/pub_releases/2005-09/ana-wcp092105.php