Environmental Factor, March 2011, National Institute of Environmental Health Sciences
Deciphering a core process in Parkinson's Disease
By Eddy Ball
During her training in the Hong group, Gao has been an author on 17 studies - 10 of them as first author. (Photo courtesy of Steve McCaw)
Hong has published over 300 peer-reviewed articles in leading biomedical journals, as well as 50 book chapters. He was a senior staff fellow at the National Institute of Mental Health before joining NIEHS in 1980. (Photo courtesy of Steve McCaw)
Two new studies from researchers at NIEHS offer insights into mechanisms of the chronic neuroinflammation that drives progressive neurodegeneration in Parkinson's disease (PD). Gradual degeneration of dopamine neurons is a hallmark of PD, the second most common neurodegenerative disease, but what drives the process - and what molecular targets may offer promise for interventions - has remained elusive.
The authors are members of the NIEHS Neuropharmacology Group(http://www.niehs.nih.gov/research/atniehs/labs/ltp/neuropharm/staff.cfm) headed by Principal Investigator Jau-Shyong Hong, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ltp/neuropharm/index.cfm) On both of the studies, Intramural Research Fellow Hui-Ming Gao, M.D., Ph.D., served as first and corresponding author. The team included Visiting Postdoctoral Fellow Hui Zhou, Ph.D., former Visiting Fellow Feng Zhang, Biologist Belinda Wilson, and Special Volunteer Wayneho Kam.
Findings from their experiments shed light on the processes that trigger the persistent neuroinflammation that is a precursor to PD and point to potential interventional targets for slowing or halting disease progression.
"We are very excited by these discoveries," Hong said of the group's work. "We hope they'll lead to a better understanding of how to mitigate or prevent the tremendous burden of this tragic disease during the critical five- to seven-year preclinical period of PD progression."
PD develops over decades before the cumulative degeneration of dopamine neurons in the substantia nigra of the brain results in a progressive worsening of motor dysfunction, characterized by tremor and impaired muscular coordination. PD, which currently is treated only symptomatically, affects more than one million people in the United States.
Gene-environment interaction is key to triggering PD
In a study(http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.1003013) published online in Environmental Health Perspectives, the scientists demonstrated an important connection between neuroinflammation and a polymorphism in the gene expressing the protein alpha-synuclein in a mutant mouse model. They compared the outcomes of wildtype and transgenic mice following exposure to the endotoxin liposaccharide (LPS), which initiated systemic and brain inflammation in the mice.
Although both groups of mice exposed to LPS initially displayed acute neuroinflammation, only the transgenic mice overexpressing alpha-synuclein developed chronic progressive degeneration of the nigrostriatal dopamine pathway, buildup of aggregated, nitrated protein, and the Lewy body-like inclusions in nigral neurons characteristic of PD.
The team tested their hypothesis further by determining that inhibition of two inflammatory enzymes - inducible nitric oxide synthase and NADPH oxidase - with compounds known as DPI and 1400W resulted in attenuation of nigral alpha-synuclein and dopaminergic neurodegeneration. "Our two-hit progressive model underlines a central role of gene-environment interactions in the development of PD," the researchers concluded.
Neutralizing the HMGB1 protein may offer an approach for treatment
In a second study(http://www.ncbi.nlm.nih.gov/pubmed/21248133) published in the Journal of Neuroscience, the research team reports isolating the protein - high-mobility group box 1 (HMGB1) - that binds to brain immune cells, known as microglial macrophage antigen complex 1 (Mac1), to activate an inflammatory cascade involving nuclear factor kappa-beta and NADPH oxidase. The lethal combination, according to the scientists, drives the persistent neuroinflammation involved in the neurodegeneration of PD.
The team exposed reconstituted mixed glial and neuron-enriched glial cell cultures to three toxins often used to create PD models - 1-Methy-4-phenylpyridium (MPP+), LPS, and the pesticide rotenone - demonstrating, for the first time, that persistent neuroinflammation is essential for progressive degeneration of dopamine neurons in PD and that it occurred only in neuron-glia mixed cultures. With neutralization of HMGB1 and genetic ablation of Mac1, the researchers were able to block over-activation of microglia and the progressive neurodegeneration of PD.
The team concluded, "Mac1 might become a promising target for the development of therapeutic agents halting the vicious cycle between uncontrolled neuroinflammation and degenerating neurons, and thereby retarding the progression of PD."
Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS.(http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.1003013) 2011. Neuroinflammation and alpha-synuclein dysfunction potentiate each other driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease. Environ Health Perspect; doi:10.1289/ehp.1003013 [Online 18 January 2011].
Gao HM, Zhou H, Zhang F, Wilson BC, Kam W, Hong JS.(http://www.ncbi.nlm.nih.gov/pubmed/21248133) 2011. HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci 31(3):1081-1092.