Insulin resistance and exendin-4 treatment for multiple system atrophy.
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.
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
Fares
F
Bassil
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
Marie-Hélène
MH
Canron
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|Service de Pathologie, CHU de Bordeaux, 33000 Bordeaux, France.
Anne
A
Vital
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
Erwan
E
Bezard
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA.
Yazhou
Y
Li
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA.
Nigel H
NH
Greig
Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD 21224, USA.
Seema
S
Gulyani
Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD 21224, USA.
Dimitrios
D
Kapogiannis
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
Pierre-Olivier
PO
Fernagut
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.|Centre de Référence Maladie Rare AMS, Hôpital Pellegrin, CHU de Bordeaux, F-33076 Bordeaux, France.|Service de Neurologie, Hôpital Pellegrin, CHU de Bordeaux, 33000 Bordeaux, France.
Wassilios G
WG
Meissner
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology; D000077270:Exenatide; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000097:blood / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D011699:Putamen / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; D010455:Peptides; D014688:Venoms; D051844:alpha-Synuclein; D000077270:Exenatide
MSA; alpha-synuclein; movement disorders; neuroprotection