Increased Choline in Brain w/DMD: Cause?

gelky at my-dejanews.com gelky at my-dejanews.com
Fri Oct 23 15:25:33 EST 1998


I'm a non-medical professional doing research on cognitive impairment in
Duchenne muscular dystrophy. Varying degrees of mental impairment are
sometimes found in patients with DMD, and recent research suggests this is
due to the effect on the brain of the same absence or faulty production of
dystrophin proteins causing muscle degeneration in the disease.

In the course of looking into this, I've come across 2 studies (abstracts
below) noting elevated levels of choline compounds in brain extracts from DMD
patients and mice. With my limited medical knowledge, I'm unsure as to the
significance of this. Is it simply a byproduct of impaired functioning? Or
might it be part of some sort of compensatory mechanism (and if so, might
increasing choline intake be beneficial)? Or something else?

Any responses will be greatly appreciated.

Following are the 2 studies mentioned above, and a few more abstracts giving
more details on the general topic:

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Neuroreport 1997 Apr 14;8(6):1435-7

Increased cerebral choline-compounds in Duchenne muscular dystrophy.


Kato T, Nishina M, Matsushita K, Hori E, Akaboshi S, Takashima S

Department of Mental Retardation and Birth Defect Research, National Institute
of Neuroscience, Tokyo, Japan.

We investigated the hypothesis that cell membrane function is abnormal in
brains of subjects with Duchenne muscular dystrophy (DMD) using
proton-nuclear magnetic resonance (NMR) spectroscopy of human brain extracts.
The total amount of choline-containing compounds was significantly higher
(about three times) than in normal controls and patients with other
myopathies, while N-acetyl-L-aspartic acid and creatine were within the
normal range. These findings indicate that abnormal cell membrane function
may be correlated with the abnormal dystrophin or lack of dystrophin in the
brain of patients with DMD.  PMID: 9172149, UI: 97316221

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J Neurol Sci 1996 Sep 15;141(1-2):13-8

An in vivo and in vitro H-magnetic resonance spectroscopy study of mdx mouse
brain: abnormal development or neural necrosis?


Tracey I, Dunn JF, Parkes HG, Radda GK

MRC Biochemical and Clinical Magnetic Resonance Unit, Department of
Biochemistry, Oxford University, UK. irene.tracey at clneuro.ox.ac.uk

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder primarily
affecting young boys, often causing mental retardation in addition to the
well-known progressive muscular weakness. Normal dystrophin expression is
lacking in skeletal muscle and the central nervous system (CNS) of both DMD
children and the mdx mouse model. The underlying biochemical lesion causing
mental impairment in DMD is unknown. 1H-magnetic resonance spectroscopy
(1H-MRS) detects choline-containing compounds, creatine and N-acetyl
aspartate (NAA) in vivo. NAA is commonly used as a chemical marker for
neurons, and a decline in NAA is thought to correlate with neuronal loss.
Control mice were compared to mdx using a combination of in vivo and in vitro
1H-MRS methods to determine whether neural necrosis or developmental
abnormalities occur in dystrophic brain. NAA levels were normal in mdx brain
compared to controls suggesting minor, if any, neuronal necrosis in
dystrophic brain. In contrast, choline compounds and myo-inositol levels were
increased, indicative of gliosis or developmental abnormalities in dystrophic
brain.	PMID: 8880686, UI: 97035030
------------------------------------------------------------------------


A few more abstracts fleshing out the general topic:


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Biochem Biophys Res Commun 1998 Aug 10;249(1):231-5

Decreased expression of brain beta-dystroglycan in Duchenne muscular dystrophy
but not in the mdx animal model.


Finn DM, Culligan KG, Ohlendieck K

Department of Pharmacology, University College Dublin, Ireland.

Abnormalities in the muscle dystrophin-glycoprotein complex are implicated in
the molecular pathogenesis of various neuromuscular disorders. Weakening of
the trans-sarcolemmal linkage between the actin membrane-cytoskeleton and the
extracellular matrix appears to trigger destabilization of the muscle cell
periphery. In addition to muscular weakness, one-third of patients suffering
from Duchenne muscular dystrophy exhibit mental retardation. Since little is
known about the pathophysiology of brain abnormalities in these patients, we
investigated the fate of the most abundant dystrophin-associated protein,
beta-dystroglycan, in the central nervous system. It was found to be present
throughout all normal brain regions studied. In contrast, this glycoprotein
was greatly reduced in brain microsomes derived from Duchenne specimens,
while it is of normal abundance in the brain from the dystrophic animal model
mdx. Deficiency in brain beta-dystroglycan might render nervous tissue more
susceptible to cellular disturbances and this may result in cognitive
impairment in some Duchenne patients.  PMID: 9705863, UI: 98381058

------------------------------------------------------------------------

Eur J Neurosci 1996 Dec;8(12):2739-47

Dystroglycan in the cerebellum is a laminin alpha 2-chain binding protein at
the glial-vascular interface and is expressed in Purkinje cells.


Tian M, Jacobson C, Gee SH, Campbell KP, Carbonetto S, Jucker M

Gerontology Research Center, National Institute on Aging, National Institute
of Health, Baltimore, MD 21224, USA.

Dystroglycan is a core component of the dystrophin receptor complex in
skeletal muscle which links the extracellular matrix to the muscle
cytoskeleton. Dystrophin, dystrophin-related protein (DRP, utrophin) and
dystroglycan are present not only in muscles but also in the brain.
Dystrophin is expressed in certain neuronal populations while DRP is
associated with perivascular astrocytes. To gain insights into the function
and molecular interactions of dystroglycan in the brain, we examined the
localization of alpha- and beta-dystroglycan at the cellular and subcellular
levels in the rat cerebellum. In blood vessels, we find alpha-dystroglycan
associated with the laminin alpha 2-chain-rich parenchymal vascular basement
membrane and beta-dystroglycan associated with the endfeet of perivascular
astrocytes. We also show that alpha-dystroglycan purified from the brain
binds alpha 2-chain-containing laminin-2. These observations suggest a
dystroglycan-mediated linkage between DRP in perivascular astrocytic endfeet
and laminin-2 in the parenchymal basement membrane similar to that described
in skeletal muscle. This linkage of the astrocytic endfeet to the vascular
basement membrane is likely to be important for blood vessel formation and
stabilization and for maintaining the integrity of the blood-brain barrier.
In addition to blood vessel labelling, we show that alpha-dystroglycan in the
rat cerebellum is associated with the surface of Purkinje cell bodies,
dendrites and dendritic spines. Dystrophin has previously been localized to
the inner surface of the plasma membrane of Purkinje cells and is enriched at
postsynaptic sites. Thus, the present results also support the hypothesis
that dystrophin interacts with dystroglycan in cerebellar Purkinje neurons. 
PMID: 8996823, UI: 97150050

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