Environmental Factor, November 2006, National Institute of Environmental Health Sciences
Extramural Guest Lecturer on PD Risk Factors
By Eddy Ball
As part of the Laboratory of Pharmacology and Chemistry (LPC) 2006-2007 Seminar Series, Donato Di Monte, M.D., director of basic research at The Parkinson Institute (TPI), spoke on October 5 in F-193. Following an introduction by Host John Hong, Ph.D., supervisory pharmacologist in the LPC, Di Monte presented to a standing-room-only audience of NIEHS scientists his latest research findings on "Risk Factors for Human Parkinsonism: Clues from Experimental Work."
For several years, Di Monte, an internist with advanced training in toxicology and biochemistry, and his colleagues have been elucidating the mechanisms of toxicant-induced neuron damage. They have used models of Parkinson's Disease (PD) triggered by exposures to MTPT, an industrial toxin and by-product of street-lab drug production, and the pesticides Rotenone and Paraquat. Their findings in cellular, rodent and non-human primate studies show promise in the search for risk factor analysis, early warning and intervention.
Epidemiological data indicate that risk for PD is age- and gender-dependent, with men more than two times as likely as women to develop the disease. Early onset of the disease is relatively rare, but incidence begins to spike at age 50 and continues to rise later in life. Di Monte and other PD researchers have hypothesized that early events may with time predispose a person to develop PD, and they are attempting to identify long-term latency risk factors for early warning signs.
Animal in vivo models using environmental inducers of PD-like symptoms demonstrated that the numbers of neurons decrease dramatically in older animals following exposures. Depending on the toxicant used, these reductions occurred in total dopamine (DA) count or in specific types of DA receptors. Age and toxicant exposure appeared to work synergistically to produce greater damage than either does by itself.
In mice studies using Paraquat, Di Monte observed a distinct sequence of exposure that suggested what Di Monte described as a "priming" effect that could be a potential target of intervention. Initial exposure activated microglial cells, which appeared to make DA neurons more susceptible to damage from a second exposure. If clinicians can reverse activation, as they have by administering the antibiotic minocycline, then neuron damage may be reduced or prevented.
Di Monte's studies also indicated that two other risk factors, exposure to the endotoxin lipopolysaccharide and the up-regulation of the enzyme known as NADPH oxidase, precede the neuron damage that takes place in PD. Both stimulated oxidative damage by producing lipid peroxides. Theoretically, the oxygen free radicals produced as a result create an underlying inflammatory condition that sets the stage for significant cell death and damage in the nigra straitum. Research within the TPI and in other centers has identified yet another risk factor, elevated iron levels of infant formula, and potentially protective agents, nicotine and nicotinic receptor agonists.
Within the past year, Di Monte and other PD researchers have taken a special interest in a "rogue" protein in the brain, a-synuclein (SNCA). SNCA appears to be initially protective when activated, but with continued up-regulation in response to toxicant exposure, it seems to trigger cell loss. SNCA up-regulation has been linked to gene mutations and may be the first major breakthrough in establishing a genetic link in PD, which accounts for approximately 10 per cent of cases. Blocking activation of SNCA could be a potentially effective intervention for patients with the disease.
During the lecture, Di Monte expressed his gratitude for institute sponsorship, noting that "NIEHS has contributed significantly to the field [of PD research]." TPI, one of three NIEHS-sponsored centers, offers unique opportunities by combining basic research and clinical settings under one roof at its Sunnyvale, Ca. headquarters. The Collaborative Centers Program for Parkinson's Disease Research has been funded since 2002 through the NIEHS Division of Extramural Research and Training.