Abstract
Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity, patterns of expression indicated involvement of certain T-cell cytokines, vascular changes, and loss of certain growth factors, with disease progression. The results demonstrate the feasibility of profiling inflammatory molecules using diseased human brain samples, and have provided additional targets to validate in relation to PD pathology.
Highlights
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder characterized by symptoms of tremor, bradykinesia, ataxia and rigidity, and is the main cause of movement disorders in the elderly
The control samples were free of Lewy body (LB) pathology; while the ILBD and PD cases had varying degrees (Table 1)
This work is the first description of large-scale unbiased multiplex quantitative protein profiling of tissue from human substantia nigra (SN) and striatum to elucidate changes in inflammatory and related molecules that might be involved in PD pathology, though this platform was used to screen sera from patients with Parkinsonian syndromes for inflammatory protein changes (Mahlknecht et al, 2012)
Summary
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder characterized by symptoms of tremor, bradykinesia, ataxia and rigidity, and is the main cause of movement disorders in the elderly. The current estimates of PD are one million cases in the U.S.A. with 60,000 cases being added each year (Parkinson’s Disease Foundaton, 2015). This leads to significant morbidity and mortality in affected individuals along with the considerable cost of healthcare for PD patients. Most of the identified mutations in α-synuclein appear to increase the risk of PD by increasing its tendency to aggregate (Polymeropoulos, 1997; Baba et al, 1998; Conway et al, 1998; Ancolio et al, 2000; Ostrerova-Golts et al, 2000; Ghosh et al, 2013; Giráldez-Pérez et al, 2014)
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