NIH Neuroscience Series Seminar

The core business of the Lab of Cellular Transport Systems (LCTS), headed by Prof. Dr. Peter Vangheluwe, is the understanding of which unique molecular properties define a specific P-type ATPase and unraveling its physiological role in health and disease. P2 ATPases - ION TRANSPORTERS LCTS built a strong track record in the research area of the P2-type ATPases, the primary cellular Ca2+ transporters. More specifically, the lab contributed to important discoveries on the structure-function relationship and physiological role of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps and the secretory pathway Ca2+- ATPase (SPCA) isoforms. P4 ATPases - ATP10B

Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synucleinpositive Lewy bodies in surviving neurons. Together with the Christine Van Broeckhoven lab we identified compound heterozygous mutations in the P4 transport ATPase class V type 10B gene (ATP10B) in 3 Early Onset PD patients. Our lab successfully established that ATP10B, previously uncharacterized, encodes a late endo-lysosomal GluCer and phosphatidylcholine (PC) lipid fippase in which patient associated compound heterozygous mutations impair functional activities of ATP10B.

P5 ATPases - Discovery of the mammalian polyamine transporters Phylogenetic analysis of P-type ATPase sequences in early genomic sequences revealed the existence of a fifth P-type ATPase subfamily, which is exclusively found in eukaryotic lineages. However, the substrate specificity and exact cellular role of the P5-type ATPases remained elusive for a long time. Several of the five human P5 ATPases have attracted considerable interest as they are implicated in human disorders. Pioneering work of our lab successfully revealed the molecular identity of ATP13A2, a P5B-ATPase, as the first identified mammalian polyamine transporter. ATP13A2 is genetically implicated in a spectrum of neurodegenerative disorders such as Kufor-Rakeb syndrome, early-onset Parkinson’s disease (PD) but also NCL and ALS. Importantly, our work demonstrates that defective lysosomal polyamine export represents a novel pathway in the molecular pathogenesis of lysosome-dependent cell death in neurodegeneration. LCTS currently has several follow-up projects running on ATP13A2, including a drug discovery program. Other P5B-ATPase isoforms are also under study, such as ATP13A3 in pulmonary arterial hypertension and ATP13A4 in neurodevelopment disorders.

For more information go to https://research.ninds.nih.gov/neuroscience-seminar-series