Objective: (i) To determine whether insulin resistance is a neuropathological feature of multiple system atrophy (MSA) and, (ii), to evaluate the therapeutic efficacy of the glucagon-like peptide-1 analogue exendin-4 on insulin resistance, alpha-synuclein (α-syn) pathology and neuron survival in transgenic MSA mice.

Background: Several studies have demonstrated impaired insulin/insulin like growth factor-1 (IGF-1) signaling and insulin resistance (i.e. decreased insulin/IGF-1 signaling) in neurodegenerative disorders. A measure of insulin resistance is the amount of the downstream effector insulin receptor substrate 1 phosphorylated at serine residues 312 (IRS-1pS312) and 616 (IRS-1pS616). Emerging evidence suggests impaired insulin/IGF-1 signaling may also occur in MSA, as illustrated by increased insulin/IGF-1 plasma concentrations in MSA patients and reduced IGF-1 brain levels in a transgenic mouse model of MSA.

Methods: IRS-1pS312 and IRS-1p616 expression were determined by immunohistochemistry in post-mortem brain tissue of MSA patients and healthy controls, as well in the brains of PLP-SYN transgenic MSA mice and wild-type littermates. To assess the efficacy of exendin-4 on insulin resistance, a separate set of PLP-SYN mice was treated (delivery over 12 weeks via Alzet pumps) with placebo, 3.5pMol/Kg/min exendin-4 or 8.5pMol/Kg/min exendin-4. Motor performance was assessed with the traversing beam task. Striatal levels of IRS-1p312, IRS-1p616, high molecular weight and full-length α-syn were quantified by Western blotting. Nigral sections were collected for tyrosine hydroxylase immunostaining and Nissl counterstaining, followed by a stereological assessment of neuron counts.

Results: IRS-1pS312 expression was increased in neurons and oligodendrocytes in the putamen of MSA patients. Similarly, IRS-1pS312 protein levels were increased in the striatum of transgenic MSA mice. We further demonstrate that the higher dose of the FDA-approved drug exendin-4 decreases insulin resistance in transgenic MSA mice and has positive effects on nigral dopamine neuron survial and α-syn load.

Conclusions: Our results suggest that exendin-4, a well-tolerated antidiabetic drug, is a promising candidate to achieve disease modification in MSA patients by mitigating insulin resistance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glucagon-like-peptide-1-analogues-for-treating-multiple-system-atrophy-a-translational-study/