|Update - Significance of an altered dendritic synthesis of the postsynaptic scaffold protein Shank1 for the pathogenesis of the Fragile X-Syndrome
by Hans-Jürgen Kreienkamp (picture left) and Stefan Kindler, 6/8/2011
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 is 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 have 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 hope to establish
whether Shank1 is a promising target for a potential treatment of the FXS.