eNews August 17, 2016

MicroRNAs and Parkinson's Disease

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.

miR-155 is upregulated in a PD mouse model

 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).

The role of miR-155 in a mouse model of PD

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.

The role of miR-155 in the microglial response to accumulated α-syn

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.

Reference:

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