Memory and synaptic deficits in Hip14/DHHC17 knockout mice

Abstract

Palmitoylation of neurotransmitter receptors and associated scaffold proteins regulates their membrane association in a rapid, reversible, and activity-dependent fashion. This makes palmitoylation an attractive candidate as a key regulator of the fast, reversible, and activity-dependent insertion of synaptic proteins required during the induction and expression of long-term plasticity. Here we describe that the constitutive loss of huntingtin interacting protein 14 (Hip14, also known as DHHC17), a single member of the broad palmitoyl acyltransferase (PAT) family, produces marked alterations in synaptic function in varied brain regions and significantly impairs hippocampal memory and synaptic plasticity. The data presented suggest that, even though the substrate pool is overlapping for the 23 known PAT family members, the function of a single PAT has marked effects upon physiology and cognition. Moreover, an improved understanding of the role of PATs in synaptic modification and maintenance highlights a potential strategy for intervention against early cognitive impairments in neurodegenerative disease.almitoylation is a posttranslational protein modification increasingly recognized as an important regulator of neuronal development, synaptic function, and plasticity (1, 2). Palmitoyl acyltransferase (PAT) enzymes regulate membrane association of proteins by catalyzing the addition of the fatty acid palmitate to cysteines via thioester bonds. Palmitoylation is readily reversible, making it an attractive candidate for a regulator of the rapid synaptic protein trafficking required for synaptic transmission and plasticity. The growing list of palmitoylated neuronal substrates includes scaffolds, ion channels, and vesicle-associated proteins, and their palmitoylation status can have dramatic effects on function and/or localization within membranes. For example, synaptic activity dynamically regulates palmitoylation of postsynaptic density protein-95 (PSD-95), influencing its clustering at postsynaptic sites (3-5), whereas palmitoylation of NMDA-and AMPA-type glutamate receptor subunits regulates their insertion, removal, and stabilization in the postsynaptic membrane (6-9). The importance of this modification within the brain is highlighted by implication of palmitoylation deficits in a number of neurological diseases including Alzheimer's disease, schizophrenia, and Huntington disease (HD) (10).To date, 23 DHHC proteins have been identified in humans. The PAT HIP14 (DHHC17) is enriched in the brain and has a number of known synaptic substrates including PSD-95, GluA1/ 2, GAD-65, SNAP-25, and synaptotagmin I (11-13), suggesting roles in pre-and postsynaptic function. Indeed, Hip14 siRNA reduces PSD-95 clustering in hippocampal cultures (12), and Hip14 loss-of-function impairs neurotransmitter release in Drosophila (14). Interestingly, Hip14 function is impaired in HD (15, 16), suggesting that some synaptic deficits observed in this disease (17-23) may arise from hypopalmitoylation of Hip14 substrates. In support of th...

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…DHHC17/HIP14 protein levels were not changed but DHHC17/HIP14 was dysfunctional in the presence of mutant huntingtin in YAC128 mice, suggesting that altered palmitoylation of huntingtin mediated by DHHC17/HIP14 may contribute to HD [226]. In addition, hip14 _ / _ mice exhibited a decrease in excitatory synapses in striatum [226] and in hippocampus [227]. Hip14 _ / _ mice also resulted in impaired hippocampal LTP and spatial memory [227], suggesting that loss of DHHC17/HIP14 may account for the cognitive symptoms in HD.…”

“…In addition, hip14 _ / _ mice exhibited a decrease in excitatory synapses in striatum [226] and in hippocampus [227]. Hip14 _ / _ mice also resulted in impaired hippocampal LTP and spatial memory [227], suggesting that loss of DHHC17/HIP14 may account for the cognitive symptoms in HD.…”

Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13 -Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation

“…For example, PSD-95 is a substrate for DHHC2, 3, 7, and 15; H-Ras and N-Ras are specific substrates of DHHC9 and 18; and huntingtin (htt) is a specific substrate of DHHC13 and 17 (Huang et al, 2009;Iwanaga et al, 2009). Loss of Palmitoylation in specific PAT substrates is important in the pathogenesis of certain diseases, including Huntington's disease (DHHC13 and 17; Singaraja et al, 2002;Yanai et al, 2006;Singaraja et al, 2011;Milnerwood et al, 2013;Sutton et al, 2013), multiple types of cancers (DHHC2, DHHC9, DHHC11, DHHC14, and DHHC20; Korycka et al, 2012), schizophrenia (DHHC8; Korycka et al, 2012), X-linked mental retardation (DHHC9 and DHHC15; Korycka et al, 2012), acute myeloid leukemia (DHHC14; Yu et al, 2011), type 1 diabetes (DHHC17; Berchtold et al, 2011), and mild hair loss and skin abnormalities (DHHC21; Mill et al, 2009).…”

The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics

“…Although several mouse models of different ZDHHC isoform mutants, hypomorphs and knockouts have been reported, each with striking phenotypes ranging from neurodegeneration 10, 46 to osteoporosis 47 , the identification of the exact molecular mechanism (i.e,, the specific protein substrate in which lack of palmitoylation results in the observed phenotype) has been generally elusive. Broadly, investigators have tried unbiased proteomic approaches 42, 43 as well as more focused candidate gene approaches.…”