Park7 is inactive in some parkinson patients

Parkinson's disease is a very debilitating disease that has a significant socio-economic impact, but it is still not known what causes it to develop. We have discovered that a familial (inherited?) form of this disease is caused by the lack of destruction of a toxic metabolite formed during sugar degradation.

Background

• Parkinson's disease is a neurodegenerative disease.

• We know that specific cells in the brain die, and that specific proteins aggregate (i.e. they accumulate in an abnormal way).

• We still have no idea why these changes occur.

• We do not have any treatment that targets the underlying mechanisms, since we do not understand enough.

• It has long been suspected that the accumulation of damage during a lifetime might contribute to the development of Parkinson's disease. However, it is unclear what these changes might be.

Specific background

• In some families, several family members develop Parkinson's disease. Some of these patients have mutations in a gene called PARK7.

• Although more than 2000 articles have been published on PARK7, its function still remained elusive.

Our discovery

• We have discovered that PARK7 prevents damage caused by a reactive compound that forms in all cells that metabolize sugar.

• Sugar is broken down in cells in a pathway that is called glycolysis. This pathway is the main pathway that cells use to generate energy.

• Glycolysis consists of a series of chemical reactions that break down sugar (glucose) via several intermediates. One of these intermediates is spontaneously forms a compound that can damage proteins (i.e. the workhorses of a cell) and metabolites (i.e. small molecules that form when our body breaks down or produces more complex structures).

• PARK7 destroys the reactive compound and thereby prevents the damage.

Why it is relevant

• Up to now we did not know which type of damage causes Parkinson's disease. We have identified the origin of one type of damage that is formed almost universally in all cells, and which can be prevented by the enzyme PARK7. This finding might lead to the development of pharmacological or dietary interventions that help patients with PARK7 defects.

• PARK7 is easily inactivated by oxidative stress that can be caused by a variety of causes (e.g. the exposure to herbicides). This suggests that loss of PARK7 function and accumulation of similar type of damage might be responsible for the formation of Parkinson's disease in a wider range of patients. As a consequence, it is conceivable that the above mentioned pharmacological or dietary interventions might also work for these patients.

• We discovered that a metabolite from glycolysis (i.e. the central way how cells break down sugar) causes damage that likely causes Parkinson's disease. It is quite rare that fundamental aspects of key metabolic pathways are being discovered. It is even rarer that these findings have direct clinical implications for a complex human disease.

• The activity of PARK7 is extremely conserved, given that the inactivation of PARK7 in flies, mice and human cell lines leads to the accumulation of damaged metabolites or proteins. Furthermore, the function of PARK7 in human cells can be replace when we reintroduce related proteins from yeast or bacteria.

Article describing this research

Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite.

Heremans IP, Caligiore F, Gerin I, Bury M, Lutz M, Graff J, Stroobant V, Vertommen D, Teleman AA, Van Schaftingen E & Bommer GT

PNAS 2022; 119(4): e2111338119

Fundings

This research was supported by WELBIO and the European Research Council (ERC - project NoMePaCa).