Impaired brain insulin signalling in Parkinson’s disease
Neuropathol Appl Neurobiol. 2021-08-17; :
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Bassil F(1)(2), Delamarre A(1)(2), Canron MH(1)(2), Dutheil N(1)(2), Vital A(1)(2)(3), Négrier-Leibreich ML(1)(2)(3), Bezard E(1)(2), Fernagut PO(1)(2)(4), Meissner WG(1)(2)(5)(6).
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(3)Service d’Anatomie Pathologique, CHU de Bordeaux, Bordeaux, France.
(4)Université de Poitiers, INSERM UMR 1084, Laboratoire de Neurosciences
Expérimentales et Cliniques, Poitiers, France.
(5)Service de Neurologie – Maladies Neurodégénératives, CHU de Bordeaux,
(6)Dept. Medicine, University of Otago, Christchurch, and New Zealand Brain
Research Institute, Christchurch, New Zealand.
AIMS: Brain insulin resistance (i.e., decreased insulin/insulin-like growth factor-1 (IGF-1) signalling) may play a role in the pathophysiology of Parkinson’s disease (PD) and several anti-diabetic drugs have entered clinical development to evaluate their potential disease-modifying properties in PD. A measure of insulin resistance is the amount of the downstream messenger insulin receptor substrate-1 that is phosphorylated at serine residues 312 (IRS-1pS312) or 616 (IRS-1pS616). We assessed IRS-1pS312 and IRS-1pS616 expression in post-mortem brain tissue of PD patients and a preclinical rat model based on viral-mediated expression of A53T mutated human α-synuclein (AAV2/9-h-α-synA53T).
METHODS: IRS-1pS312 and IRS-1pS616 staining intensity were determined by immunofluorescence in both neurons and glial cells in the substantia nigra pars compacta (SNc) and putamen of PD patients and controls without known brain disease. We further explored a possible relation between α-synuclein aggregates and brain insulin resistance in PD patients. Both insulin resistance markers were also measured in the SNc and striatum of AAV2/9-h-α-synA53T rats.
RESULTS: We found higher IRS-1pS312 staining intensity in nigral dopaminergic neurons and a trend for higher IRS-1pS312 staining intensity in putaminal neurons of PD patients. We observed no differences for IRS-1pS616 staining intensity in neurons or IRS-1pS312 staining intensity in glial cells. IRS-1pS312 showed high co-localisation within the core of nigral Lewy bodies. Like PD patients, AAV2/9-h-α-synA53T rats showed higher IRS-1pS312 staining intensity in the SNc and striatum than controls, whereas IRS-1pS616 was not different between groups.
CONCLUSIONS: Our results provide evidence for brain insulin resistance in PD and support the rationale for repurposing anti-diabetics for PD treatment.
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