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.