With a $106,800 grant from FRAXA Research Foundation over 2 years, Drs. Stephan Kindler and Hans-Jurgen Kreieinkamp studied a protein, Shank1, which is overabundant in fragile X syndrome.
Postsynaptic signaling events are believed to be the starting point of long-term changes in synaptic transmission, which accompany all forms of learning and memory. In the fragile X syndrome, the lack of FMRP leads to excessive synthesis of proteins in neuronal dendrites, affecting postsynaptic protein composition and ultimately synaptic function. Comparing the postsynaptic protein structure of wildtype and FMRP deficient mice, we identified a set of molecules, which are enriched in postsynaptic regions after loss of FMRP.
One protein that is significantly increased in abundance is Shank1, which is a rather large scaffold protein connecting various types of glutamate receptors, signaling proteins and cytoskeletal filaments. Biochemical experiments indicate that FMRP physically associates with Shank1 mRNAs, is co-transported with these transcripts into dendrites and represses their translation. Increased levels of Shank1 are likely to be relevant for the pathogenesis of the fragile X syndrome as Shank1 contributes to the formation of dendritic spines during neuronal development and stabilizes synapses on nascent dendritic spines. Thus, an overabundance of Shank1 could prevent the physiological elimination of synapses, which is compromised in fragile X patients and FMRP deficient mice.
Therefore, our hypothesis was that FMRP regulates Shank1 synthesis close to postsynaptic sites, and that loss of this regulatory role in fragile X patients interferes with the pruning of synapses, a developmental process that is essential for proper wiring of the nervous system.
To put this theory to the test, we eliminated one (of two) Shank1 allels in FMRP deficient mice, thereby reducing Shank1 mRNA and protein levels. By analyzing these mice with respect to dendrite morphology, synaptic function and behavior, we hoped to establish whether Shank1 is a promising target for a potential treatment of the FXS.