Targeting Protein Palmitoylation as a Possible Regulator in Neurological Diseases

Signalling events between proteins, as well as protein localization, are highly and specifically regulated by the post-translational modifications (PTMs) that they can transiently harbour. Of these PTMs, phosphorylation, glycosylation and acetylation have been widely studied and characterized.

Protein lipidation, the covalent attachment of a lipid group to a protein, is much less studied, but thought to be equally important.

S-Palmitoylation is a reversible PTM whereby palmitate is attached to proteins at cysteine residues through a reversible thioester linkage, and is the most abundant mammalian lipid PTM.

In addition to its well established important role in fundamental biology, S-palmitoylation has been associated with multiple neurological diseases, including Huntington’s disease, schizophrenia and Alzheimer’s disease, which are all disorders with a high unmet need for (new) therapeutic strategies.

In contrast to more tractable PTMs (e.g. acetylation, phosphorylation), technological challenges limit progress of our understanding of the effect of protein lipidation on protein function, and how removal of palmitate from proteins is regulated.

Therefore, I will develop new chemical biology and proteomics tools to study the regulation of protein lipidation, focusing on S-palmitoylation, aiming to reveal how these modifications affect brain proteins, especially those that are linked to neurological diseases.

I will develop 1) a substrate trapping methodology to identify substrates of the enzymes that remove palmitate from proteins (palmitoyl thioesterases); 2) substrate inspired activity-based probes (ABPs) that allow substrate validation and identification of palmitoyl thioesterases for disease relevant substrates; and 3) investigate the molecular identity of the lipid PTMs on dynamically regulated S-palmitoylated proteins involved in neurodegenerative disorders by native top-down mass-spectrometry.

Together, these innovative approaches will provide a unique platform to study the role and regulation of S-palmitoylation the brain and may uncover new therapeutic strategies to treat neurological disorders.