Zinc increases the protective function of albumin against Parkinson’s disease

Revealing the interaction of zinc with a critical transport protein underscores the need to study biological pathways under physiologically relevant conditions.

It has long been thought that heavy metals in the body induce aggregation of disease-related proteins, but a KAUST study shows that this is not always the case.

It turns out that zinc ions optimize the ability of human serum albumin (HSA), a transport protein abundant in the body, to better prevent α-synuclein aggregation, a process directly linked to Parkinson’s disease.

The finding should “open new avenues for preventative treatments,” says Samah Al-Harthi, Ph.D. Student whose work won a best poster award at the International Symposium on Frontiers in Molecular Science.

The unexpected role of zinc discovered by Al-Harthi only became clear after she and her mentor Łukasz Jaremko studied the metal’s effects on HSA, the main carrier of zinc in blood plasma and spinal fluid, under physiologically relevant conditions.

In unrealistically large amounts, zinc tends to accelerate the aggregation of α-synuclein, a neuronal protein implicated in Parkinson’s disease. Other scientists had shown this in the past. But under the biologically plausible experimental conditions contemplated by Al-Harthi, the metal does interact with HSA to produce the opposite effect.

Using a cutting-edge imaging technique known as proton-less nuclear magnetic resonance spectroscopy, Al-Harthi and colleagues showed that zinc binding alters the chaperone function of HSA, a multifunctional molecule that plays a role in blocking α-synuclein accretion. Zinc ions, in particular, resulted in stronger interactions of HSA with the aggregation-prone fragments of α-synuclein, a change that attenuates fibrillization and slows the toxic process of protein deposition that can lead to neurodegeneration.

The results are consistent with another recent report by Al-Harthi and Jaremko on the complex interplay between fatty acids, zinc ions and HSA. This report also required careful consideration of human physiology and experimental conditions to show how a particular fatty acid, regularly used to treat diabetes, can help stabilize HSA function to correct metabolic irregularities.

Together, the work of Al-Harthi and Jaremko underscores the need to think about biological complexity when studying intricate molecular pathways. “These medically relevant biomolecules cannot be studied in isolation if we want to discover medically relevant insights that may be of future therapeutic use,” says Al-Harthi.

“Biology is not as simple as the laboratory flask. That,” she says, “is what drives and motivates my studies.”

Recent work is published in International Journal of Biological Macromolecules and frontiers in chemistry.