Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Abstract

Posttranslational modifications of proteins are important regulatory processes endowing the proteins functional complexity. Over the last decade, numerous studies have shed light on the roles of palmitoylation, one of the most common lipid modifications, in various aspects of neuronal functions. Major players regulating palmitoylation are the enzymes that mediate palmitoylation and depalmitoylation which are palmitoyl acyltransferases (PATs) and protein thioesterases, respectively. In this review, we will provide and discuss current understandings on palmitoyation/depalmitoylation control mediated by PATs and/or protein thioesterases for neuronal functions in general and also for Alzheimer's disease in particular, and other neurodegenerative diseases such as Huntington's disease, schizophrenia and intellectual disability.

CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

“…Synaptic protein palmitoylation is also affected by seizures and anticonvulsants (18,55,56), and several DHHC PAT mutations and substrates have been linked to neurological and neuropsychiatric disorders, including Huntington's, schizophrenia, and X-linked intellectual disability, that are characterized by altered synaptic plasticity (48,57,58). Our findings here reveal novel cross-talk between postsynaptic Ca 2ϩ signaling, palmitoylation, and phosphorylation pathways that are required for synaptic plasticity and thus have implications for understanding these diseases.…”

The Interplay of Cofactor Interactions and Post-translational Modifications in the Regulation of the AAA+ ATPase p97

“…Of these three lipid modifications, only palmitoylation is reversible, thus allowing for a more dynamic regulation of protein function with respect to trafficking, localization, stability, aggregation, and interaction with effectors (reviewed in Cho and Park, 2016). Lipidation increases the hydrophobicity of proteins, which promotes the association of the modified proteins with the plasma membrane and other membranes such as those of the ER, mitochondria, Golgi, and endosomes.…”

“…Palmitoylation, which is catalyzed by palmitoylacyltransferases (PATs), also known as DHHC enzymes and is reversed by palmitoyl protein thioesterases, is the covalent attachment of the 16 carbon fatty acid palmitate to the side chain of specific cysteine residues of target proteins via a thioester bond. Dependent on the target protein palmitoylation functions in a large variety of cellular processes including subcellular trafficking as well as signal transduction and aberrant palmitoylation has been associated with Alzheimer's disease, Huntington's disease and other neurodegenerative disorder (Cho and Park, 2016). …”

Palmitoylation mechanisms in dopamine transporter regulation

“…Many proteins with essential functions in neurotransmission and synaptic plasticity are palmitoylated (Duncan and Gilman, 1998; el-Husseini Ael and Bredt, 2002; Fang et al , 2006; Fukata et al , 2004; Hayashi et al , 2005; Keller et al , 2004), and dysregulation of palmitoylation is associated with multiple neurological disorders, including intellectual disability, Huntington disease, Alzheimer disease, schizophrenia, and the lysosomal storage disease infantile neuronal ceroid lipofuscinosis (reviewed in Cho and Park, 2016). In many cases these diseases are caused or associated with dysregulation of the acyl transferases or thioesterases that cause inappropriate palmitoylation of target proteins, suggesting that similar dysregulation of palmitoylation inputs into DAT could have strong impacts on its associated functions.…”