Insulin resistance and exendin-4 treatment for multiple system atrophy.
Brain. 2017-03-14; 140(5): 1420-1436
DOI: 10.1093/brain/awx044
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1. Brain. 2017 May 1;140(5):1420-1436. doi: 10.1093/brain/awx044.
Insulin resistance and exendin-4 treatment for multiple system atrophy.
Bassil F(1)(2), Canron MH(1)(2), Vital A(1)(2)(3), Bezard E(1)(2), Li Y(4), Greig
NH(4), Gulyani S(5), Kapogiannis D(5), Fernagut PO(1)(2), Meissner
WG(1)(2)(6)(7).
Author information:
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000
Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux,
France.
(3)Service de Pathologie, CHU de Bordeaux, 33000 Bordeaux, France.
(4)Translational Gerontology Branch, Intramural Research Program, National
Institute on Aging, Baltimore, MD 21224, USA.
(5)Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD 21224,
USA.
(6)Centre de Référence Maladie Rare AMS, Hôpital Pellegrin, CHU de Bordeaux,
F-33076 Bordeaux, France.
(7)Service de Neurologie, Hôpital Pellegrin, CHU de Bordeaux, 33000 Bordeaux,
France.
See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this
article. Multiple system atrophy is a fatal sporadic adult-onset
neurodegenerative disorder with no symptomatic or disease-modifying treatment
available. The cytopathological hallmark of multiple system atrophy is the
accumulation of α-synuclein aggregates in oligodendrocytes, forming glial
cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling
(IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported
in other neurodegenerative disorders such as Alzheimer’s disease. Increasing
evidence also suggests impaired insulin/IGF-1 signalling in multiple system
atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in
multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic
mouse model of multiple system atrophy. We here tested the hypothesis that
multiple system atrophy is associated with brain insulin resistance and showed
increased expression of the key downstream messenger insulin receptor substrate-1
phosphorylated at serine residue 312 in neurons and oligodendrocytes in the
putamen of patients with multiple system atrophy. Furthermore, the expression of
insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was
more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast,
it was not different between both groups in the temporal cortex, a less
vulnerable structure compared to the putamen. These findings suggest that insulin
resistance may occur in multiple system atrophy in regions where the
neurodegenerative process is most severe and point to a possible relation between
α-synuclein aggregates and insulin resistance. We also observed insulin
resistance in the striatum of transgenic multiple system atrophy mice and further
demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated
and Federal Drug Agency-approved antidiabetic drug, has positive effects on
insulin resistance and monomeric α-synuclein load in the striatum, as well as
survival of nigral dopamine neurons. Additionally, plasma levels of exosomal
neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to
serine residue 312 in humans) negatively correlated with survival of nigral
dopamine neurons in multiple system atrophy mice treated with exendin-4. This
finding suggests the potential for developing this peripheral biomarker candidate
as an objective outcome measure of target engagement for clinical trials with
glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our
observation of brain insulin resistance in multiple system atrophy patients and
transgenic mice together with the beneficial effects of the glucagon-like
peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this
innovative treatment into a clinical trial.
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DOI: 10.1093/brain/awx044
PMID: 28334990 [Indexed for MEDLINE]