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Keywords:

  • cytoskeleton;
  • glutamate receptors;
  • neurological disorders;
  • postsynaptic density;
  • synapse

Abstract

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

The postsynaptic density (PSD) is a specialized electron-dense structure underneath the postsynaptic plasmamembrane of excitatory synapses. It is thought to anchor and cluster glutamate receptors exactly opposite to the presynaptic neurotransmitter release site. Various efforts to study the molecular structure of the PSD identified several new proteins including membrane receptors, cell adhesion molecules, components of signalling cascades, cytoskeletal elements and adaptor proteins with scaffolding functions to interconnect these PSD components. The characterization of a novel adaptor protein family, the ProSAPs or Shanks, sheds new light on the basic structural organization of the PSD. ProSAPs/Shanks are multidomain proteins that interact directly or indirectly with receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. These interactions suggest that ProSAP/Shanks may be important scaffolding molecules of the PSD with a crucial role in the assembly of the PSD during synaptogenesis, in synaptic plasticity and in the regulation of dendritic spine morphology. Moreover the analysis of a patient with 22q13.3 distal deletion syndrome revealed a balanced translocation with a breakpoint in the human ProSAP2/Shank3 gene. This ProSAP2/Shank3 haploinsufficiency may cause a syndrome that is characterized by severe expressive language delay, mild mental retardation and minor facial dysmorphisms.

Abbreviations used:
CIRL/CL1

calcium-independent latrotoxin receptor

CortBP

cortactin-binding proteins

IP3

inositol 1,4,5-trisphosphate

MAGuK

membrane-associated guanylate kinase

mGluR1

metabotropic glutamate receptor 1

PRC

proline-rich cluster

ProSAP1

and 2, proline-rich synapse-associated proteins

PSD

postsynaptic density

SAM

sterile alpha motif

SAPAP/GKAP

SAP90/PSD-95-associated protein/guanylate kinase-associated protein

SSTR2

somatostatin receptor 2

SSTRIP

somatostatin receptor-interacting proteins.

Chemical synapses in the central nervous system (CNS) are highly specialized asymmetric cell-to-cell contacts between neurons. The efferent, presynaptic side of the contact is characterized by the accumulation of synaptic vesicles at the active zone of the synapse, the afferent postsynaptic part by a submembraneous electron-dense meshwork, the postsynaptic density (PSD). At excitatory synapses, this structure is about 40–50 nm thick (Harris and Stevens 1989) and harbours molecules that are involved in postsynaptic signal transduction as well as synaptic plasticity (Ziff 1997). The PSD is thought to be a molecular device to receive and integrate synaptic signals and transduce them into the postsynaptic cell. Excitatory synapses utilize glutamate as the major neurotransmitter and different types of glutamate receptors are highly concentrated at the postsynaptic site. For a long time it was not known how these receptors are arranged and clustered in the postsynaptic membrane and how these receptor clusters are linked to the cytoskeleton. The identification of the MAGuK (membrane-associated guanylate kinase) family of synaptic proteins, e.g. SAP90/PSD-95, SAP102 or chapsyn-110/PSD-93, and the demonstration of their interaction with the C-terminus of distinct NMDA receptor subunits via PDZ domains have shed the first light on possible receptor clustering mechanisms at postsynaptic sites (for review see Ziff 1997; Garner et al. 2000; Kennedy 2000). Subsequent work has revealed that these synaptic adaptor proteins MAGuKs may connect postsynaptic signalling elements, e.g. neuronal NO synthase or SynGAP, linker molecules, like GKAPs/SAPAPs or CRIPT as well as cell adhesion molecules, e.g. neuroligins or semaphorins, to the NMDA receptor complex (Garner et al. 2000; Kennedy 2000; Inagaki et al. 2001; Schultze et al. 2001). More recently the characterization of the ProSAP/Shank family of PSD proteins and the identification of binding partners for these proteins provided new insights into the molecular organization of the PSD. The scope of this review is to summarize and discuss the emerging basic principles of how different types of glutamate receptors, cell adhesion molecules and proteins of intracellular signalling cascades are organized at a higher order in the PSD by ProSAPs/Shanks and how these protein clusters are attached to the cytoskeleton.

Structure, expression and synaptic localization of ProSAP/Shank proteins

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

ProSAPs/Shanks were initially characterized by different groups (see Table 1 for synonymous names). In yeast-two-hybrid screens members of this family were identified as proteins interacting with SAPAP/GKAP (SAP90/PSD-95-associated protein/guanylate kinase-associated protein) and/or the metabotropic glutamate receptor 1 (mGluR1)-binding protein Homer/VESL (Shank 1–3: Naisbitt et al. 1999; Tu et al. 1999; Synamon: Yao et al. 1999), cortactin-binding proteins (CortBP: Du et al. 1998), somatostatin receptor-interacting proteins (SSTRIP: Zitzer et al. 1999b) and partial sequences were deposited in public databases as Cl1-interacting proteins (Spank1–3: Tobaben et al. 2000). In a screen for proteins that are enriched in the PSD fraction of rat brain, members of the family identified as core PSD proteins interacting with SAPAP/GKAP and named proline-rich synapse-associated proteins (ProSAP1 and 2: Boeckers et al. 1999a,b; Gundelfinger and tom Dieck 2000).

Table 1.  Synonyms for ProSAP/Shank family members
Name, species Synonymous names
  1. 1, 2Shanks, SH3 domain and ankyrin repeat-containing protein; Naisbitt et al. (1999); Tu et al. (1999); 3Yao et al. (1999); 4,5ProSAP, proline-rich synapse-associated protein 1 and 2; Boeckers et al. (1999ab); 6SSTRIP, somatostatin receptor interacting protein; Zitzer et al. (1999b); 7CortBP-1, cortactin-binding protein 1; Du et al. (1998); 8Tobaben et al. (2000).

Shank1, rat1,2Synamon, rat3SSTRIP, human6Spank2, rat8
Shank2, rat1,2ProSAP1, rat4,5CortBP1, rat7Spank3, rat8
Shank3, rat1,2ProSAP2, rat4,5 Spank1, rat8

ProSAPs/Shanks are multidomain proteins that are characterized by an impressive set of predicted protein–protein interaction domains (Fig. 1). Prototypical family members harbour 5–6 N-terminal ankyrin (ANK) repeats followed by a well-conserved SH3 (Src homology 3) domain and a PDZ (PSD-95/DLG/ZO1) domain. Their C-terminal halves include several proline-rich clusters (PRC), a cortactin-binding domain (ppI) and a SAM (sterile alpha motif) domain. The molecular diversity among all family members is further amplified via alternative splicing of ProSAP/Shank mRNAs and the use of alternative start sites for transcription and/or translation (Fig. 1) resulting in each case in various ProSAP/Shank isoforms (Boeckers et al. 1999a; Lim et al. 1999). For instance, there are Shank1 isoforms lacking the SAM domain (Shank1b) or short ProSAP1/CortBP-1 isoforms that start with the PDZ domain (Du et al. 1998; Boeckers et al. 1999a). In rat brain, it has been shown by in situ hybridization with splice variant-specific probes that expression of individual isoforms generated from the same ProSAP gene varies in distinct sets of neurons and is developmentally regulated (Boeckers et al. 1999a; unpublished observation).

image

Figure 1. Domain structure and splice isoforms of the ProSAP/Shank family of synaptic proteins. ProSAP/Shank proteins are defined by a specific pattern of highly conserved (up to 95% identity) protein–protein interaction domains. N-terminal ankyrin repeats (ANK) are followed by an SH3 (Src homology3) domain and a PDZ (PSD-95/DLG/ZO-1) domain. To date, it is unclear whether Shank2/ProSAP1 isoforms with ANK repeats exist. The C-terminal part of the proteins is characterized by several mostly conserved proline-rich clusters (PRC). One of those clusters is called ppI domain and mediates the interaction with cortactin (Du et al. 1998). The ppI domain seems to be absent in Shank1. All proteins have a SAM (sterile alpha motif) domain at the C-terminus of the molecule. All ProSAP/Shank transcripts are subject to differential expression (alternative splicing and processing or alternative transcription/translation initiation or termination) leading to multiple isoforms for each family member. The hitherto known splice/processing sites are depicted here (Boeckers et al. 1999a; Lim et al. 1999). In Shank2/ProSAP1 short exons can be inserted [2–4] and a longer form with the SH3 domain (ProSAP1A) can be discerned from a shorter ProSAP1/Shank2 transcript starting with the PDZ domain (ProSAP1, starting at point [1]). In addition, a cDNA clone has been identified missing a large part of the C-terminus (ending at [5]). In Shank3/ProSAP2 a long and a short (starting at [1]) form is known, which could also be identified in Shank1 (starting at [2]). In Shank1 alternative splicing could also be observed in the 5′UTR of the transcripts with an unknown effect on protein translation [1] and a short exon can be inserted next to the PDZ domain [3]. Interestingly the SAM domain can be spliced out so that long and short Shank1 proteins with and without a SAM domain (Shank1a-d, Lim et al. 1999) are expressed.

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Despite the high sequence identity of the ProSAP/Shank family members the expression pattern of individual members is distinct and cell-type specific. All ProSAP/Shank proteins can be found in brain, but only Shank1 seems to be brain-specific (Lim et al. 1999). ProSAP1/Shank2 is expressed in neurons, glia, various endocrine cells (Redecker et al. 2001) and can also be detected in liver and kidney. Hence, ProSAP2/Shank3 transcripts could be identified at different expression levels in all tissues examined (Lim et al. 1999). In the brain all ProSAP/Shank proteins are coexpressed in cortical and hippocampal neurons while in other brain areas neuron-specific expression of individual ProSAP/Shank members can be observed (Boeckers et al. 1999b; unpublished observation).

Also, with respect to the subcellular localization of the transcripts differences among individual ProSAP/Shank mRNAs have been found. A dendritic localization of Shank1 transcripts was described initially by Zitzer et al. (1999a) and Sheng and Kim (2000) in the hippocampus. In experimental paradigms for synaptic plasticity, long-lasting modification of synaptic strength requires protein synthesis (Kang and Schuman 1996), suggesting that newly synthesized proteins contribute to the modification of synaptic efficacy. In this respect, a key finding was the observation of polyribosomes underneath synapses at the base of dendritic spines (Steward and Levy 1982) indicating that protein synthesis may occur locally in dendrites upon stimulation. With the ProSAP/Shank mRNAs, the list of dendritic RNAs (Steward and Schuman 2001) is extended by transcripts coding for an important new class of PSD components.

Efforts to determine the subcellular localization of individual ProSAP/Shank proteins by immunostaining of hippocampal cultures or immunoelectron microscopy revealed that all three family members are present at the PSD of excitatory synapses (Boeckers et al. 1999a; Naisbitt et al. 1999; Valtschanoff and Weinberg 2001). In an elegant study, Valtschanoff and Weinberg (2001) could demonstrate that ProSAP/Shank proteins are concentrated in deeper parts of the PSD as compared with SAP90/PSD-95 and SAPAP/GKAP. This is in good agreement with models that describe the molecular set-up of excitatory synapses based on protein–protein interactions (Fig. 2). The developmental appearance of ProSAP/Shank proteins at the PSD has been studied in hippocampal culture and in the developing rat brain (Du et al. 1998; Boeckers et al. 1999a; Lim et al. 1999; Naisbitt et al. 1999). After an initial accumulation of the proteins in the cell cytoplasm and growth cones at early stages, a rapid localization at the PSD is observed between postnatal day 6–10. However, information both about the synaptic targeting signals within the three ProSAP/Shanks and about the temporal appearance of proteins interacting with ProSAP/Shanks at the PSD is still incomplete. For Shank1 it has been shown that the PDZ domain is mandatory for a proper targeting to the synapse (Sala et al. 2001) and that its localization at the PSD follows the formation of the SAP90/PSD-95-GKAP complexes (Naisbitt et al. 1999; Sheng and Kim 2000). In contrast, ProSAP1/Shank2 targeting to the PSD occurs very early during synaptogenesis, and precedes the incorporation of the SAP90/PSD-95-NMDA complex (Boeckers et al. 1999a). Moreover, targeting of ProSAP1 appears to be independent from the PDZ domain (TMB and EDG, unpublished observation).

image

Figure 2. ProSAP/Shank proteins as a core component of the PSD (see also Table 2). The N-terminal ankyrin repeats of ProSAP/Shank interact with sharpin and with the α-subunit of brain spectrin (fodrin). The PDZ domain can interact with several other synaptic proteins including the somatostatin receptor 2 (SSTR2), the calcium independent α-latrotoxin receptor (CIRL) and – most importantly – the GKAPs/SAPAPs. The latter can bind to the guanylate kinase domain of MAGuKs, e.g. SAP90/PSD-95, and thereby may tie NMDA receptors, Kainate receptors (KAR) and cell adhesion molecules (e.g. Neuroligin and Semaphorin 4) into the PSD. A proline-rich region of dynamin-2 interacts with a serine-rich ProSAP/Shank sequence. Specific short proline-rich motifs define the interaction with Homer (thereby connecting mGluR1 with ProSAP/Shank) and with cortactin. The interaction with α-fodrin and cortactin mediates the attachment of the above mentioned receptor clusters to the ‘actin-based’ cytoskeleton at excitatory synapses.

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ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

One of the key structures of ProSAP/Shank proteins is the central PDZ domain, which is found in all known isoforms of all three family members (Fig. 1). This domain is nearly identical among the family members but shows significant sequence differences compared with other PDZ domains (Boeckers et al. 1999a; Lim et al. 1999). As described above, several independent yeast-two-hybrid screens led to the initial identification of ProSAP/Shank proteins via the PDZ domain interaction using C-terminal bait constructs of known proteins. Best characterized is the ProSAP/Shank interaction with a family of PSD proteins called SAPAP1–4/GKAP (Boeckers et al. 1999b; Naisbitt et al. 1999; Yao et al. 1999). The C-terminal amino acids -QTRL mediate the binding with this PDZ domain. Mutational analysis revealed a C-treminal consensus sequence of X-T/S-X-L/I. SAPAP/GKAP proteins were originally identified as SAP90/PSD-95 interacting proteins by binding to the guanylate kinase domain of this PSD scaffolding protein (Kim et al. 1997; Takeuchi et al. 1997). Therefore SAPAP/GKAPs interconnect ProSAP/Shank proteins with scaffolding molecules of the MAGuK family of proteins. Since SAP90/PSD-95 is able to cocluster different receptor molecules, ion channels and cell adhesion molecules via its PDZ, SH3 or GuK domains, i.e. NMDA receptors, kainate receptors, Shaker-type K+ channels, neuroligins or semaphorins sema4C and sema4F (Garner et al. 2000; Gundelfinger and tom Dieck 2000; Inagaki et al. 2001; Schultze et al. 2001; Sheng and Sala 2001), these primary cluster units are connected with the ProSAP/Shanks. This indirect physical link between ProSAP/Shanks and the NMDA receptor has been independently confirmed by affinity purification and proteomic analysis of the NMDA receptor complex (Husi et al. 2000). Interestingly, two further membrane-bound receptors can interact directly with the PDZ domain, i.e. somatostatin receptor 2 (SSTR2; Zitzer et al. 1999a,b) and the calcium-independent latrotoxin receptor (CIRL, Kreienkamp et al. 2000; Cl1, Tobaben et al. 2000). At present it is, however, not clear, whether this interaction occurs in the PSD. Because one PDZ domain can interact only with one of these partners it remains to be clarified, whether a certain interaction is restricted to a specific population of cells or specific subdomains within a cell or whether several binding partners within the PSD can compete for ProSAP/Shank's PDZ domain depending on their local abundance and binding affinity.

One of the proline-rich clusters of ProSAP/Shank proteins can mediate direct interaction with the EVH1 domain of Homer, a scaffolding molecule that links mGluR1s with inositol 1,4,5-trisphosphate (IP3) receptors (Tu et al. 1998, 1999). The consensus sequence PPXXF is found in all ProSAP/Shank family members and a Homer dimer connects mGluRs to ProSAP/Shank via its two EVH1 domains. Therefore ProSAPs/Shanks can cross-link Homer and SAP90/PSD-95 complexes in the PSD. Again, this finding is consistent with data obtained by Husi et al. (2000) when analysing affinity-isolated NMDA receptor-PSD-95 complexes. Sheng and Kim (2000) reported that the SH3 domain binds to GRIP, an AMPA receptor binding protein in GST pull-down experiments. However, no further evidence for this interaction has been presented to date. Another, yet unproven, possible ProSAP/Shank complex including all three glutamate receptors could be structurally based on the SAPAP/GKAP-mediated interconnection with the SAP97 complex binding to AMPA receptors (Leonard et al. 1998; see also Gundelfinger and tom Dieck 2000).

Recently, Okamoto et al. (2001) reported a direct interaction of ProSAP/Shank proteins with dynamin-2. Mapping experiments using the yeast-two-hybrid system revealed that the C-terminal proline-rich domain of dynamin-2 interacts with a short serine-rich sequence conserved within all ProSAP/Shank family members. Interaction with ProSAP/Shank seems to be restricted to dynamin-2, which is a widely expressed dynamin isoform. Interestingly hippocampal neurons expressing dominant inhibitory GTPase mutants of dynamin-2 showed an extensive inhibition of clathrin-dependent AMPA-receptor internalization (Carroll et al. 1999). The binding of dynamin-2 to ProSAP/Shank may lead to a specific localization of dynamin molecules underneath the postsynaptic membrane possibly regulating membrane turnover and recycling of glutamate receptors.

A specific feature of the multidomain ProSAP/Shank family of scaffolding molecules is their ability to indirectly bind to the actin-based cytoskeleton in a manner that allows the attachment of glutamate receptor multiprotein complexes to cytoskeletal structures. Cortactin is an F-actin binding protein that is enriched in cell matrix contact sites, lamellipodia and growth cones of cultured neurons. Moreover, cortactin is known to play a crucial role in the rearrangement of cytoskeletal structures in response to extracellular and intracellular stimuli (Wu and Parsons 1993). The SH3 domain of cortactin interacts specifically with a SH3 binding motif known as ppI (PPψPXKP) domain (Du et al. 1998), that is identical in ProSAP1/Shank2 and ProSAP2/Shank3 but seems to be absent from Shank1. Further studies will show how the ProSAP/Shank–cortactin interaction contributes to dynamic changes of spines and PSDs with respect to morphological plasticity.

Additionally, the N-terminal ANK repeats can connect ProSAP2/Shank3 and Shank1/SSTRIP to the membrane-associated cytoskeleton by binding to spectrin repeat 21 of α-fodrin (also known as brain α-spectrin; Bockers et al. 2001). α-Fodrin, a multidomain protein that contains 22 spectrin repeats, one SH3 domain, and two EF-hand calcium binding motifs, is a major constituent of the PSD (Carlin et al. 1983) and interacts with actin and calmodulin. An interesting feature of α-fodrin is its selective calmodulin-dependent processing in response to the elevation of calcium levels (Harris and Morrow 1990), synaptic activity or both. This calpain protease-mediated processing has been widely used as a marker for ongoing synaptic activity (Vanderklish et al. 2000) and should also interfere with the ProSAP/Shank interaction of α-fodrin. To date, one can only speculate on how fodrin processing in response to local activity enables structural rearrangements of the PSD (Boeckers et al. 2001).

Another novel interacting protein of the ProSAP/Shank ankyrin repeats named sharpin, has been identified by Lim et al. (2001). In a yeast-two-hybrid screen the cDNA of this 43–44-kDa protein could be cloned using the N-terminus of Shank1 as bait. Sharpin is a PSD protein and characterized by a coiled-coil domain and a region that is highly homologous to RBCK1, a protein kinase C-binding protein (Lim et al. 2001). Sharpin is expressed in all tissues examined and has the ability to self-associate. A possible sharpin head-to-head multimerization might be a mechanism by which ProSAP/Shank proteins are cross-linked. A different mechanism by which ProSAP/Shank can bind in a homomeric or heteromeric fashion has been described by Naisbitt et al. (1999) in providing experimental evidence that ProSAP/Shank proteins can interact in a tail-to-tail manner via their SAM domains. Potential ProSAP/Shank interactions in the PSD are depicted in Fig. 2 and summarized in Table 2.

Table 2.  Domains and interacting proteins of the ProSAP/Shank family
Domain Interacting partnerInteracting domainFunctionCitation
ANKAnkyrin repeatsα-FodrinSpectrin Repeat 21Coupling to the actin based cytoskeletonBoeckers et al. (2001)
SharpinAA172-305Oligomerization of ProSAP/Shank by self association of Sharpin?Lim et al. (2001)
SH3Src homology 3 domain?   
PDZPSD95/ DLG/ZO1 domainGKAP/ SAPAPC-term -QTRLCoupling to NMDA-R and cell adhesion molecules via MAGuKsNaisbitt et al. (1999); Boeckers et al. (1999b); Yao et al. (1999)
CIRL/Cl1C-term -VTSLReceptor clustering?Kreienkamp et al. (2000); Tobaben et al. (2000)
SSTR2C-term -QTSIReceptor clusteringZitzer et al. (1999a)
AA 1430- 1459 (ProSAP2)EEVDSRSSSDHHL ETTSTISTVSSISTLSDynamin-2C-terminal proline rich regionVesicle recycling? Recycling of glutamate receptors?Okamoto et al. (2001)
AA 1381-LVPPPE EFANHomer/VESLEVH1 domainCoupling to mGluRs and/or IP3 Tu et al. (1999)
1391(ProSAP2)   receptors 
AA 1485-ppI-DomainCortactinSH3 domainCoupling to the actin based cytoskeletonDu et al. (1998)
1494 (ProSAP2)KPPVPPKPK    
SAMSterile alpha motifProSAP/ShankSAM domainOligomerization of ProSAP/ShankNaisbitt et al. (1999)

Table 2 lists proteins interacting with ProSAP/Shank family members including the interacting domains of both partners. Of note, it is still unknown whether there is a ProSAP1/Shank2 isoform with ANK repeats; Shank1 is missing a ‘typical’ ppI domain but contains sequences similar to the ppI domain. A possible interaction with cortactin remains to be determined (Fig. 2).

ProSAP/Shank proteins and morphological plasticity

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

Synapses are dynamic structures; since phenomena like learning and memory are thought to be directly related to morphological changes of synaptic structures, the molecular mechanisms underlying these synaptic alterations are of particular interest. In this respect experiments published recently by Sala et al. (2001) are of fundamental significance since they have demonstrated that over-expression of Shank1 alters spine morphology in transfected primary hippocampal neurons. Transfection with Shank1 not only promotes the maturation of dendritic spines but in addition also changes the spine shape to a mushroom-like appearance. Interestingly, this effect seems to be spine specific, i.e. spine number or the shape of the dendritic tree was not affected. In contrast, dominant negative Shank1 mutants caused a reduction of spine size but also spine density. Moreover, the Homer binding site of Shank1 appears to be crucial for the induction of morphological changes, leading to the hypothesis that the recruitment of IP3 receptors and/or the local concentration of small GTPases may be downstream signals for local morphological rearrangements. In the light of these data, dendritic mRNA transport of ProSAP/Shank and subsequent local translation following synaptic activation (see above) may be important for local structural synaptic changes after excitation of individual synapses.

A role for ProSAP/Shank proteins in neurological disease?

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

Considering the role of ProSAP/Shank proteins as ‘master scaffolding molecules’ (Sheng and Kim 2000) and as key proteins involved in dynamic changes of synaptic morphology (Sala et al. 2001), it is not surprising that mutations affecting members of the ProSAP/Shank family may result in pathological disorders. The ProSAP2 gene is localized on chromosome 22q13.3 and has recently been proposed as one of the candidate genes (Wong et al. 1997) for a neurogenetic deletion syndrome (the 22q13.3. deletion syndrome) initially described by Watt et al. (1985). This disease, cytogenetically characterized by a microdeletion of the long arm of chromosome 22, is associated with generalized developmental delay, normal or accelerated growth, hypotonia, severe delays in expressive speech, and mildly dysmorphic facial features (Nesslinger et al. 1994; Wong et al. 1997; Prasad et al. 2000). There are only about 25 published cases in the literature but one has to expect far more affected patients since only a very low percentage of patients showing these symptoms are tested for microdeletions (Flint et al. 1995). Striking evidence for a direct genetic relation of this syndrome with a defect of the ProSAP2/Shank3 gene has now been provided by a study from Bonaglia et al. (2001). The authors report about a patient with the clinical signs of a 22q13.3 syndrome. Genetic analysis revealed a balanced translocation between chromosome 12 and 22 causing a disruption of the ProSAP2/Shank3 gene at exon 21. Therefore haplo-insufficiency for ProSAP/Shank3 is most likely the cause for the pathological state.

Further studies, particularly in knock-out and transgenic mouse models for the ProSAP/Shank family of proteins, could provide data on the molecular mechanisms causing these neurological deficits. Furthermore the identification of a gene defect responsible for the 22q13.3 deletion syndrome could open new ways for diagnostic and therapeutic strategies for the syndrome.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References

The authors would like to acknowledge the financial support from Deutsche Forschungsgemeinschaft (DFG Bo 1718/1–1 and DFG Bo 1718/2–1) and IZKF at the UKM Münster (F1) to TMB, and DFG/SFB426/A1, DFG/Kr 1879/2–1 and the European Commission (QLG3-CT-2001–01181) to MRK and EDG.

References

  1. Top of page
  2. Abstract
  3. Structure, expression and synaptic localization of ProSAP/Shank proteins
  4. ProSAP/Shanks constitute the molecular interface between postsynaptic membrane proteins and the ‘actin-based’ cytoskeleton
  5. ProSAP/Shank proteins and morphological plasticity
  6. A role for ProSAP/Shank proteins in neurological disease?
  7. Acknowledgements
  8. References
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