University of Dundeen scientists have uncovered the molecular mechanisms and targets under the effect of a specific gene mutation involved in Parkinson’s disease development and which could prove to be strong targets for new therapies and even early disease detection. The paper entitled “Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1” was published in The EMBO Journal.
Mutations in the PINK1 gene have been associated with the development of Parkinson’s disease (PD). The gene encodes PTEN-induced putative kinase 1, an enzyme that protects cells against stress caused by mitochondrial dysfunction. Researchers have linked PINK1 activity to neuronal protections, and its loss of function is associated with the onset of Parkinson’s symptoms. Until now, the hypothetical targets of PINK1 activity were still unknown.
Previous research identified the presence of Lewy bodies, hallmark structures in PD, in the brains of families with PINK1 mutations. Moreover, loss of PINK-1 genetic activity in mouse and C. elegans models led to excess of mutant α-synuclein, a protein also linked to PD pathology. Over-expression of Rab8A and related Rab GTPases proteins was also found to be involved in the rescue of α-synuclein-related neurodegeneration.
A molecular link between PINK1 and α-synuclein pathways has been suggested but never discovered. Through a series of state-of-the-art technology, scientists led by Drs. Miratul Muqit and Matthias Trost, have now uncovered a novel pathway controlled by PINK1, where this gene targets and alters Rab GTPases activity, which in turn regulates cell growth and survival, and protects against neurodegeneration in brain cells.
“Parkinson’s disease is at present incurable and it is vital we understand the molecular mechanisms in order to design the next generation of therapeutics against the disease. In previous work we had outlined a single pathway for PINK1, but the discovery of an entire family of Rabs as PINK1 targets indicates a more complex network of pathways that, if disrupted, renders brain cells vulnerable to stress and ultimately to the development of Parkinson’s,” explained Dr. Muqit in a university press release.
Based on their results, researchers hypothesize that Rabs could be strong therapeutic targets for PD therapy drug design, while monitoring modifications in these proteins can be used as a biomarker for early PD diagnosis.