This grant builds upon the research from a prior grant: Functional Characterization of ATP13A2, a P-type Transport ATPase Involved in Neurodegeneration
Promising Outcomes of Original Grant:
One of the objectives of the original study was the development of biochemical and cell-based assays for measuring ATP13A2 protein activity. We largely achieved this goal, which represents an important milestone for the study of ATP13A2. The biochemical assay now allows us, for the first time, to characterize the enzyme properties of ATP13A2 and disease. This method also enables a screening for the transported substrate of ATP13A2, which represents a remaining bottleneck for understanding the role of ATP13A2 in neurodegeneration. Finally, the developed cellular assays and cell lines offer a unique opportunity to study the interaction between ATP13A2 and alpha-synuclein.
Objectives for Supplemental Investigation:
With the biochemical tools we developed in the first study, we will test whether ATP13A2 is an ion transporter or a lipid flippase (i.e. transporter). As a lipid flippase, ATP13A2 might affect the interaction of alpha-synuclein with intracellular membrane compartments, which might explain the protective effect of ATP13A2 towards alpha-synuclein neurotoxicity. This hypothesis will be explored using our stable cell lines with ATP13A2 overexpression and with tissue obtained from ATP13A2 knock-out pre-clinical models.
Importance of This Research for the Development of a New PD Therapy:
Our work has the potential to provide a major break-through in understanding the pathological role of ATP13A2. It will lead to a better understanding of lysosomal dysfunction in PD, which contributes to a reduced clearance of misfolded proteins such as alpha-synuclein. More specifically, we aim to understand how ATP13A2 protects against alpha-synuclein neurotoxicity. Such insights might open the path to design novel therapeutic approaches for Parkinson’s disease to protect or restore neurons in neurodegenerative disorders. Moreover, our new biochemical methods will be useful as a tool for predicting whether genetic mutations in ATP13A2 are risk factors for Parkinson’s disease or related Lewy Body disorders.
Final Outcome
ATP13A2 is a protein linked to an inherited, early-onset form of Parkinson's disease (PD). ATP13A2 protects brain cells from alpha-synuclein -- a sticky protein that clumps in the brains of people with PD -- and from toxic effects of Mn2+ and Zn2+, which increase the risk of Parkinson's. Therefore, ATP13A2 might be therapeutic in PD. In this study, we identified a fragment of ATP13A2 crucial to its activity, i.e., in whose absence ATP13A2 is unable to function. This fragment activates ATP13A2 when it comes in contact with special molecules, called signaling lipids. We also demonstrated that in conditions of mitochondrial stress -- stress-induced changes in mitochondria, cell's energy generators -- ATP13A2 becomes activated and protects brain cells. The presence of the signaling lipids is required for this activation. Finally, we investigated why ATP13A2 protects brain cells from alpha-synuclein toxicity and found evidence that ATP13A2 may prevent alpha-synuclein attachment to cellular membranes. This study, therefore, is essential to understanding the role, conditions and mechanisms of ATP13A2 activation. The results further support ATP13A2 activation as a therapeutic strategy.
June 2013
Publications
van Veen S, Sorensen DM, Holemans T, Holen HW, Palmgren MG, Vangheluwe P. Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders. Front Mol Neurosci. 2014;7:48.
Holemans T, Sorensen DM, van Veen S, et al. A lipid switch unlocks Parkinson's disease-associated ATP13A2. Proc Natl Acad Sci USA. 2015;112(29):9040-9045.
A follow-up paper is also in preparation.
Presentations
Our work on ATP13A2 was recently presented during two consecutive presentations from our lab in August 2014 at the latest P-type ATPase meeting in Lunteren (The Netherlands). This is an important meeting in the transporter field, held every three years, and the back-to-back presentations provided important exposure for our work.
"Unlocking ATP13A2 activity" -- Peter Vangheluwe
"Phylogenetic analysis, topology and intracellular localization of the five human P5-type ATPase isoforms, the least characterized family of P-type transporters" -- Tine Holemans (Tine Holemans won the best presentation award for her achievement)
Patents
ZL914005 - Patent application number GB1415337.3, filed 29 Aug 2014. "SCREENING METHODS FOR ATP13A2 ACTIVATORS"