Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNpc) and an accumulation of α-synuclein (α-syn) protein. Recent studies support neuroinflammation as an important factor that drives PD pathogenesis. MHC class II cell surface receptor polymorphisms, microgliosis, widespread T-cell infiltration, and proinflammatory cytokine expression, including TNF, IL-1β, IL-6 and IFN-γ, all contribute to a proinflammatory microenvironment in the PD-affected SNpc. Increasing evidence implicates microRNAs as critical regulators in immune and inflammatory-related neurodegenerative disorders, such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In a study published recently in The Journal of Neuroscience, a group led by Dr. David G. Standaert at The University of Alabama at Birmingham discovered that microRNA-155 (miR-155) is significantly up-regulated in a mouse model of PD. They subsequently examined the proinflammatory role of miR-155 in the neurodegeneration associated with PD.
With growing evidence that atypical microRNA expression levels are observed in other neurodegenerative disorders such as MS, ALS, and AD, Dr. Standaert's group used a PCR-array approach to examine the expression of inflammation- and autoimmune-associated microRNAs in a mouse model of PD. C57BL/6J (000664) mice were infected with an adeno-associated virus expressing human α-syn (AAV2-SYN) in the SNpc, which resulted in increases in both human α-syn mRNA and protein. Following infection, enhanced miR-155 expression was observed in the investigator’s array, which they verified by quantitative PCR. miR-155 was already known as a key microRNA modulator of neuroinflammation, and is induced by various proinflammatory stimuli such as LPS, INF-γ and TNF activity. miR-155 contributes to proinflammatory signaling cascades that ultimately stimulate upregulation of IL-1, IL-6, TNF-α, and inducible nitric oxide synthase (iNOS).
To evaluate the downstream effects of increased miR-155 expression in PD, Dr. Standaert's group administered AAV2-SYN or AAV2-GFP (a green fluorescent protein-expressing control) into the SNpc of both C57BL/6J (000664) and a miR-155-null mouse, B6.Cg-Mir155tm1.1Rsky/J (007745). Four weeks after infection, significant increases in MHCII and CD68, which are both markers for microgliosis, were observed in the AAV2-SYN-infected wild-type mice but not in the AAV2-SYN-infected miR-155 knockout mice. In a separate cohort of mice that were examined 6 months post-AAV2-SYN infection dopaminergic neurons in the infected C57BL/6J mice were reduced 30%, whereas only a 3% decrease was observed in the infected miR-155 knockout mice. These data suggest miR-155 is required for dopaminergic neural degenerations induced by prolonged α-syn protein overexpression.
To directly assess the role of miR-155 in α-syn-induced microglia activation, primary microglia cultures were treated with sonicated α-syn fibrils, which activate glial cells in vitro. In fibril-treated microglial cultures from C57BL/6J mice, expression of both MHCII and iNOS increased. In contrast α-syn fibrils failed to stimulate MHCII and iNOS expression in primary microglia cultures from miR-155 knockout mice. To determine if restoring miR-155 expression was sufficient to elicit an inflammatory response, microglia cultures from miR-155 knockout mice were treated with an oligonucleotide mimic of miR-155. Although the oligonucleotide mimic by itself did not activate microglia cultures from miR-155 knockout mice, MHCII and iNOS expression were observed when the mimic-treated cultures were subsequently stimulated with α-syn fibrils.
Taken together, these studies suggest that miR-155 plays a key role in the stimulating an inflammatory response following aberrant α-syn overexpression. Additionally, the reduced degeneration of dopaminergic neurons in the SNpc of miR-155 null mice that overexpress α-syn suggests that miR-155 may be a viable therapeutic target for delaying or halting PD-related neurodegeneration.
Thome AD, Harms AS, Volpicelli-Daley LA, Standaert DG. 2016. microRNA-155 regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease. The Journal of Neuroscience. PMID: 26911687