Micro-scale control of oligodendrocyte morphology and myelination by the intellectual disability-linked protein acyltransferase ZDHHC9

Mutations in the ZDHHC9 gene cause XLID (Baker et al., 2015; Raymond et al., 2007; Masurel-Paulet et al., 2014). XLID-associated ZDHHC9 mutations include nonsense mutations and missense mutations affecting key amino acids, as well as splice site mutations, insertions, and deletions that result in frameshifts. Importantly, all these genetic changes are predicted to be loss-of-function. These findings suggest that ZDHHC9 is essential for higher brain function.

Given that many XLID genes are neuronally enriched (Devys et al., 1993; Budreck and Scheiffele, 2007; Toya et al., 2023; Rusconi et al., 2008; Guarnieri et al., 2017; Murphy et al., 2006; Bienvenu et al., 2002), an a priori hypothesis is that ZDHHC9 acts in neurons. However, patients with ZDHHC9 mutations have grossly normal gray matter (GM) but reduced brain white matter (WM) volume, especially in the corpus callosum (CC) (Baker et al., 2015; Raymond et al., 2007; Masurel-Paulet et al., 2014). ZDHHC9 mutations are also linked to cerebral palsy, a condition in which intellectual disability is often associated with WM impairment (WMI) (Jiang et al., 2019; Odding et al., 2006; van Eyk et al., 2019; McMichael et al., 2015). These findings raise the possibility that ZDHHC9 may be crucial for normal WM development and/or proper function of oligodendrocytes (OLs), the myelin-forming CNS glia abundant in WM. Notably, Zdhhc9 knockout (KO) mice exhibit WM volume reductions and seizure-like activity (Kouskou et al., 2018; Shimell et al., 2019), as well as behavioral phenotypes seen in other mouse models of ID (Kouskou et al., 2018). Thus, Zdhhc9 KO mice have the potential to serve as an excellent model for human ZDHHC9 mutations. However, their phenotype is yet to be fully characterized.

ZDHHC9 codes for a protein acyltransferase (PAT), an enzyme that catalyzes the modification of protein cysteine residues with palmitate and related fatty acids. This process, termed palmitoylation (also known as S-palmitoylation or S-acylation), plays a critical role in targeting proteins to specific subcellular membrane locations (Linder and Deschenes, 2007). Nearly 30 years ago, it was reported that major myelin proteins in the nervous system, including Proteolipid protein (PLP), Myelin basic protein (MBP), Myelin-associated glycoprotein (MAG), and Myelin oligodendrocyte glycoprotein (MOG), are palmitoylated (Bizzozero and Good, 1990; Agrawal et al., 1983). However, at that time, methods were lacking to define the roles of palmitoylation of these proteins in myelin formation and function. Later proteomic studies revealed many other palmitoylated myelin proteins (Kang et al., 2008; Wan et al., 2013; Gorenberg et al., 2022; Edmonds et al., 2017), and an isolated study suggested that palmitoylation targets myelin proteins to the plasma membrane of cultured OLs (Schneider et al., 2005). Despite these findings, little is known regarding how myelin protein palmitoylation is regulated and the functional importance of this process for higher brain function.

We hypothesized that ZDHHC9-dependent palmitoylation plays a critical role in proper myelination and WM formation. Consistent with this notion, we report that ZDHHC9 is the most highly expressed PAT in mouse and human OLs. Moreover, ZDHHC9 localizes to puncta in OL processes that are likely Golgi outposts, whereas other PATs tested and ZDHHC9 XLID mutant forms are restricted to OL cell bodies. These findings may explain why ZDHHC9 loss of function cannot be compensated by other PATs. In mice lacking Zdhhc9, we did not detect changes in OL lineage cell generation or total MBP expression levels, but we found that at the micro-scale Zdhhc9 KO OLs are dysmorphic and myelin ultrastructure is highly abnormal, with both hypo- and hypermyelination of axons in WM tracts. We show that with the help of Golga7, a ZDHHC9 partner protein that also localizes to Golgi outposts, ZDHHC9 robustly palmitoylates the major myelin protein MBP, and that MBP palmitoylation is impaired in Zdhhc9 KO brain. Palmitoyl- and total levels of another myelin protein, Myelin-associated Glycoprotein (MAG) are also affected by Zdhhc9 KO, suggestive of a broader deficit in myelin protein regulation and organization in these mice. Interestingly, the XLID mutant ZDHHC9-P150S still palmitoylates MBP in a Golga7-dependent manner in transfected non-neuronal cells, raising the possibility that impaired subcellular localization in OLs, rather than impaired catalytic activity, may cause or contribute to WM abnormalities in some cases of ZDHHC9-associated XLID. Together, our findings provide new insights into mechanisms of ZDHHC9-associated XLID and the palmitoylation-dependent control of myelination, a process first reported decades ago, but about which almost nothing is known.

Genetic factors are central to intellectual disability (Vorstman and Ophoff, 2013; Vissers et al., 2016), as exemplified by the increasing number of known XLID-associated genes (Renpenning et al., 1962; Amir et al., 1999; Billuart et al., 1998; Neri et al., 2018). However, knowledge of the cellular/molecular processes controlled by XLID-associated gene products is often limited. The cognitive deficits and epilepsy that are hallmarks of ZDHHC9-associated XLID are often ascribed to malformations of neocortical gray matter (Stevenson et al., 2013; Guerrini and Dobyns, 2014; Lim and Crino, 2013; Zhang et al., 2010; Juric-Sekhar and Hevner, 2019). Indeed, ZDHHC9 is expressed in a subset of forebrain neurons (Doyle et al., 2008), and ‘Zdhhc9 knockdown’ primary hippocampal neurons display impaired dendritic branching and an altered ratio of excitatory-to-inhibitory synapses (Shimell et al., 2019). However, there is an increasing appreciation that ID can also result from impaired WM formation and/or function (Shangguan et al., 2019; Wong, 2019; Yu et al., 2008; Spencer et al., 2005; Soldán and Pirko, 2012). Consistent with this notion, both ZDHHC9 and its partner protein Golga7 are far more highly expressed in OLs than in other CNS cell types, in both mice and humans (Figure 1E and F, Zhang et al., 2014; Zeisel et al., 2018; Zhang et al., 2016). In support of a key role for ZDHHC9 in normal WM formation and function, we found that Zdhhc9 KO does not affect axon number in the CC, but greatly impacts microscale OL morphology and myelin ultrastructure (Figures 4—6). We recognize that using conventional Zdhhc9 KO mice, in which Zdhhc9 is globally deleted, cannot directly address whether impaired myelination in these mice is due to a cell-autonomous role for ZDHHC9 in OLs, a role for ZDHHC9 in neurons, or a combination of these factors. However, the impaired OL morphology and maturation seen in culture conditions after acute Zdhhc9 loss (Figure 7) supports the first of these possibilities. While a conditional KO mouse could more directly help test the OL-autonomous role of ZDHHC9 in vivo, in this study, we focused on conventional KO mice to more accurately mirror the situation in human patients with ZDHHC9 loss or mutation.

It is perhaps surprising that, despite the clear changes in OL morphogenesis, we did not detect changes in overall numbers of OPCs or OLs in Zdhhc9 KO mice. However, we cannot exclude the possibility that such changes could be revealed by different methods. In addition, different OL subtypes express different subsets of other marker genes (Soldán and Pirko, 2012) and it remains possible that Zdhhc9 loss preferentially directs OL maturation towards or away from one or more of these subtypes. Furthermore, we cannot exclude the possibility that assessment of other brain regions might also reveal differences in OPC and/or OL numbers in Zdhhc9 KO mice. Lastly, we also note that acute Zdhhc9 loss in cultured OLs causes more striking phenotypes than seen with KO mice in vivo. However, it is not uncommon for acute knockdown to cause more dramatic effects than germline KO, possibly due to longer-term compensatory mechanisms in vivo (George et al., 2015; Elias et al., 2006). Together, though, our findings suggest that OL and WM abnormalities could significantly contribute to ZDHHC9-associated XLID.

We also recognize that although Zdhhc9 loss affects OL morphology both in vitro and in vivo, the specific nature of these changes differs between the two systems (compare Figures 4 and 7). However, several non-mutually exclusive factors could account for these differences. First, morphology in vivo may well be influenced by the axons and/or other extrinsic components around each OL that are not present in our primary cultures. Second, OL growth in vivo is highly 3-dimensional, whereas growth in culture is largely 2-dimensional – it may be difficult to support formation of spheroids (by definition, a 3-dimensional structure) in the latter situation. Finally, ZDHHC9 is absent in vivo from the beginning of development until the time points examined, whereas in our cultured OL experiments, Zdhhc9 shRNA is virally delivered to OPC cultures at DIV2 and likely acutely affects Zdhhc9 expression predominantly in committed OLs (following the switch to differentiation medium at DIV3). These differences may also affect the ability of other PATs or, potentially, palmitoylation-independent subcellular processes, to compensate for Zdhhc9 loss. Further experiments, perhaps involving longitudinal imaging of the development of fluorescently labeled OLs in the two systems, could provide more insights into how Zdhhc9 loss affects OL morphological elaboration.

Based on behavioral milestones, patients with ZDHHC9-associated XLID have been diagnosed as young as two years of age (Schirwani et al., 2018), suggesting that ZDHHC9 is important for higher brain function during early development. Consistent with this notion, we observed dysmyelination (both hyper and hypomyelination) in P30 mice, approximately equivalent to a 3-year-old human (Dutta and Sengupta, 2016). These findings suggest that the myelin abnormalities observed in adult Zdhhc9 KO mice (Figure 6) are due to impaired initial myelination, rather than impaired myelin maintenance, and further support the use of Zdhhc9 KO mice as a model for human ZDHHC9-associated XLID.

Although difficult to prove causation in a global, conventional KO line, the myelin abnormalities in Zdhhc9 KO mice are also associated with behavioral impairments that have some overlap with human patients with ZDHHC9-associated XLID. Most notably, Zdhhc9 KO mice have seizures, reminiscent of the rolandic epilepsy reported in many human patients with ZDHHC9 mutation (Baker et al., 2015; Shimell et al., 2019). Zdhhc9 KO mice also have impaired latency to reach a hidden platform in the Morris Water Maze (MWM), a task designed to assess spatial learning (Kouskou et al., 2018). However, the KO mice do not differ significantly in reference memory in a subsequent probe trial, suggesting that, despite the increased latency, they do learn the location of the platform as effectively as wt (Kouskou et al., 2018). In addition, performance in both the open field and in an elevated plus maze (EPM, in which the KO mice spend significantly more time in the open arms) suggests that Zdhhc9 KO mice also have decreased levels of anxiety (Kouskou et al., 2018). Decreased anxiety is reported in several other mouse models of ID (Zang et al., 2009; Samaco et al., 2008; Escorihuela et al., 1998; Peier et al., 2000; Altafaj et al., 2001). Finally, Zdhhc9 KO mice spend significantly less time on a hanging wire task (Kouskou et al., 2018), a phenotype consistent with hypotonia, a phenotype also reported in patients with ZDHHC9 mutation (Raymond et al., 2007; Masurel-Paulet et al., 2014; Han et al., 2017). Like reduced anxiety, hypotonia is seen in several human neurodevelopmental conditions and relevant mouse models (see Kouskou et al., 2018 and references therein for a fuller discussion). While either OL-specific conditional KO of Zdhhc9 or OL-specific rescue in a KO background would be required to determine causation. However, these findings are consistent with a model in which the impaired myelination in the absence of Zdhhc9 causes behavioral abnormalities reminiscent not just of ZDHHC9 mutation in humans, but also in other forms of ID.

Zdhhc9 is also expressed at higher levels than other PATs in OLs (Figure 1C, E and F), potentially explaining much of the impact of Zdhhc9 loss in these cells. However, it is also intriguing that ZDHHC9wt localization in OLs differs markedly from that of other PATs examined, and of three ZDHHC9 XLID mutants (Figure 2). These findings suggest that specific subcellular localization of ZDHHC9wt is central to the role of this PAT in OLs and explain why other PATs, and ZDHHC9 XLID mutant forms cannot compensate for loss of ZDHHC9wt. This notion is further supported by our findings that the XLID-associated P150S and, to a lesser extent, R96W mutant forms of ZDHHC9 are still capable of palmitoylating MBP in cotransfected cells. Indeed, despite its reduced catalytic activity in an in vitro assay (Mitchell et al., 2014), ZDHHC9-P150S does not differ significantly from ZDHHC9wt in its ability to palmitoylate MBP, or to autopalmitoylate, in our cell-based assay. This residual autopalmitoylation, which was also observed in Mitchell et al., 2014, suggests that ZDHHC9-P150S might still be capable of palmitoylating MBP and/or other substrates in OLs, if it were to be targeted to the correct subcellular location. Impaired subcellular targeting thus represents an additional possible contributory factor, not mutually exclusive with impaired catalytic activity, to explain impairments in ZDHHC9-associated XLID. More broadly, these results emphasize the importance of precise subcellular localization in palmitoylation-dependent regulation, a key take home message from prior studies by ourselves and others e.g., (George et al., 2015; Zhang and Thomas, 2024; Furne et al., 2006).

What, then, is the identity of the puncta in OL subcellular processes to which ZDHHC9wt can localize, but which other PATs and ZDHHC9 XLID mutants cannot? Our immunostaining results with subcellular organelle markers suggest that these puncta represent Golgi outposts or satellites, and that ZDHHC9’s key partner Golga7 also localizes to this location (Figure 2, Figure 2—figure supplement 2A; Govind et al., 2021; Fu et al., 2019). Golgi outposts have long been known in neurons (Horton and Ehlers, 2003), and we previously reported that ZDHHC9 localizes to such structures in primary hippocampal neurons (Shimell et al., 2019). Golgi outposts were also recently described in OLs (Wang and Gleeson, 2020). However, the function of these structures in OLs remains to be fully determined, so the role(s) of ZDHHC9 at this subcellular organelle is challenging to infer. Nonetheless, we speculate that ZDHHC9 could be involved in either or both of the best-described roles of Golgi outposts, protein glycosylation and microtubule nucleation, for the following reasons. First, ZDHHC9-positive Golgi outposts in OL processes are also positive for the enzyme Mannosidase II, suggesting they represent sites at which protein glycosylation is regulated (Figure 2—figure supplement 2B). In addition, although ZDHHC9 colocalization with TPPP, a protein implicated in microtubule nucleation, is less apparent (Figure 2—figure supplement 2C), knockout/knockdown of either ZDHHC9 (Figures 4 and 7) or TPPP (Fu et al., 2019) affects branching and complexity of OL processes, a process that involves microtubule nucleation. However, more investigation is needed to determine the functions of Golgi outposts in OLs, in order to define the associated contribution of ZDHHC9.

Another intriguing question is whether and how the loss of ZDHHC9 action at Golgi outposts might contribute to the myelination deficits we observed in Zdhhc9 KO mice (Figures 5 and 6). Our sparse genetic labeling studies revealed that Zdhhc9 KO OL processes are distended, with numerous spheroid-like swellings (Figure 5). We reason that these spheroids are enclosed by the OL lipid membrane because if the membrane were ruptured, the EGFP signal would likely diffuse. This, in turn suggests that the caliber of the OL process at the position of the spheroid is grossly abnormal, i.e., the membrane has hyper-expanded. Given that OL membrane growth during myelination extends in two directions, i.e., spiral growth to the axonal surface and longitudinal growth along the axon, it is possible that spheroid-like structures are formed by uneven myelin growth. We recognize that we cannot yet conclude whether and how spheroid formation might relate to the myelination deficit in Zdhhc9 KO mice that we observe by EM (Figure 6). However, it is not inconceivable that the hypo- and hypermyelination of Zdhhc9 KO axons seen in single-plane EM cross-sections (Figure 6) represents this same distension phenotype, observed using a different method. Although beyond our current technical abilities, we speculate that EM-based reconstruction in three dimensions would reveal regions of both hypo- and hypermyelination of individual callosal axons in Zdhhc9 KO mice.

How, though, might Zdhhc9 loss cause dysmyelination? Several myelin proteins are palmitoylated, and we found that a ZDHHC9/Golga7 complex palmitoylates the major myelin protein MBP and that MBP palmitoylation is reduced in forebrain WM of Zdhhc9 KO mice (Figure 8). Given that palmitoylation can sort proteins to the myelin membrane (Schneider et al., 2005), the simplest explanation might be that impaired palmitoylation of MBP, and potentially other myelin proteins, in the absence of ZDHHC9 affects myelin structure per se. It would be of considerable interest to investigate whether and how Zdhhc9 loss alters the distribution of specific MBP splice variants. However, the anti-MBP antibody used in this study recognizes all forms of MBP, not just the specific splice variants whose palmitoylation is affected by Zdhhc9 loss. Specifically assessing nanoscale distribution of these splice variants would require a way (e.g. anti-MBP splice form-specific antibodies that are compatible with immuno-EM) to distinguish these variants from other, non-palmitoylated forms of MBP. Developing such an antibody could greatly facilitate future studies of nanoscale MBP distribution in the presence and absence of ZDHHC9.

We also observed slight but significant reductions in palmitoyl- and total levels of MAG in the absence of ZDHHC9 (Figure 8—figure supplement 1A and B), which may also contribute to impaired myelination. In contrast, ZDHHC9 loss did not alter palmitoyl- or total levels of Cadm4, a myelin protein whose palmitoylation is ascribed to the Golgi-localized PAT ZDHHC3 (Chang et al., 2022; Figure 8—figure supplement 1C and D). This latter finding suggests that, although ZDHHC9 loss may affect additional myelin proteins, gross, widespread dysregulation of myelin protein levels and/or palmitoylation in the absence of ZDHHC9 is unlikely. Importantly, several mutant forms of ZDHHC9 fail to localize to Golgi outposts in OLs and lead to XLID, even when showing apparently normal catalytic activity. This latter observation is consistent with a model in which ZDHHC9 action at OL Golgi outposts is critical for normal myelination. An additional factor to consider, however, is that the key ZDHHC9 substrate(s) may not be the myelin proteins themselves, but rather other proteins that act at Golgi outposts to direct myelin proteins to the correct region of the myelin membrane and/or to ensure uniform distribution of myelin proteins within that membrane. Another non-mutually exclusive possibility is that ZDHHC9 acts at Golgi outposts but indirectly, for example, to drive the expression of myelin protein genes. A comparison of WT and Zdhhc9 KO palmitoyl-proteomes could help determine which of these possibilities (which are not mutually exclusive) best accounts for impaired myelination in the absence of ZDHHC9.

Interestingly, despite their marked differences in basal catalytic activity (as assessed by autopalmitoylation), wt and all XLID forms of ZDHHC9 appear to show enhanced activity (measured by both auto- and MBP palmitoylation) in the presence of Golga7, suggesting that the association with Golga7 (which also localizes to Golgi outposts) is central to ZDHHC9 activity. This model is also highly consistent with the biased expression of Golga7 in OLs, compared to other CNS cell types (Figure 1E and F). Moreover, XLID-associated mutant forms of ZDHHC9 also show reduced protein stability and are impaired in their ability to form complexes with Golga7 (also known as Golgi Complex Protein 16 kDa; GCP16)(Nguyen et al., 2023). ZDHHC9 XLID mutations may thus affect ZDHHC9 trafficking to Golgi outposts per se, but alternatively, or in addition, may decrease formation/stabilization of ZDHHC9/Golga7 complexes at these locations. Either or both of these mechanisms, which are not mutually exclusive, may contribute to impaired MBP palmitoylation and/or myelination deficits caused by ZDHHC9 mutation.

In summary, we reveal an unexpectedly non-heterogeneous expression of Zdhhc9 in both mice and humans, with biased expression in mature OLs. Moreover, within OLs, WT ZDHHC9 localizes uniquely compared to other PATs examined, and to XLID-associated forms of ZDHHC9. Although we did not detect changes in overall OL numbers or gross myelin staining, we found that Zdhhc9 loss greatly impairs OL morphology and myelination at the microscale. These findings provide new insights into mechanisms of ZDHHC9-associated XLID and into other conditions marked by WMI.

RNA-Seq data files have been uploaded to the European Nucleotide Archive (ENA) under accession code PRJEB19341. All other data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Hey-Kyeong Jeong

   Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Estibaliz Gonzalez-Fernandez

   Competing interests

   No competing interests declared

2. Estibaliz Gonzalez-Fernandez

   Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Contributed equally with

   Hey-Kyeong Jeong

   Competing interests

   No competing interests declared

3. Ilan Crawley

   Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Julia M Coakley

   Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Jinha Hwang

   Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

6. Dale DO Martin

   Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Present address

   Department of Biology, University of Waterloo, Waterloo, Canada

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

7. Shernaz X Bamji

   Department of Cellular and Physiological Sciences, Life Sciences Institute and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada

   Contribution

   Resources, Funding acquisition

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0102-9297

8. Jong-Il Kim

   Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Supervision

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7240-3744

9. Shin H Kang

   1. Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States
   2. Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Investigation, Writing – original draft, Funding acquisition, Writing – review and editing

   For correspondence

   shin.kang@temple.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3692-9802

10. Gareth M Thomas

    1. Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, United States
    2. Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, United States

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    gareth.thomas@temple.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-3183-8431

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