Matrix Metalloproteinases and Minocycline: Therapeutic Avenues for Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common known genetic form of intellectual disability and autism spectrum disorders. FXS patients suffer a broad range of other neurological symptoms, including hyperactivity, disrupted circadian activity cycles, obsessive-compulsive behavior, and childhood seizures. The high incidence and devastating effects of this disease state make finding effective pharmacological treatments imperative. Recently, reports in both mouse and Drosophila FXS disease models have indicated that the tetracycline derivative minocycline may hold great therapeutic promise for FXS patients. Both models strongly suggest that minocycline acts on the FXS disease state via inhibition of matrix metalloproteinases (MMPs), a class of zinc-dependent extracellular proteases important in tissue remodeling and cell-cell signaling. Recent FXS clinical trials indicate that minocycline may be effective in treating human patients. In this paper, we summarize the recent studies in Drosophila and mouse FXS disease models and human FXS patients, which indicate that minocycline may be an effective FXS therapeutic treatment, and discuss the data forming the basis for the proposed minocycline mechanism of action as an MMP inhibitor.

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

“…Importantly, mammalian Mmps are upregulated in neurological disorders (Huntley, 2012), including multiple sclerosis (Agrawal et al, 2008), epilepsy (Pollock et al, 2014;Wilczynski et al, 2008) and Fragile X syndrome (FXS), the most common heritable determinant of intellectual disability and autism spectrum disorders (Gatto and Broadie, 2011). Similar to the mouse FXS model (Bilousova et al, 2009;Sidhu et al, 2014), the Drosophila FXS disease model exhibits Mmp dysfunction as an underlying cause of neurodevelopmental phenotypes (Siller and Broadie, 2012). Neural defects in the Drosophila FXS model, including impairments in both morphological and functional synaptic differentiation (Doll and Broadie, 2014) are remediated by pharmacological or genetic Mmp inhibition (Siller and Broadie, 2011).…”

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…Our findings with timp demonstrate the utility of variability as a metric to uncover regulatory nodes that preserve the functional resiliency of the nervous system. By pharmacologically correcting timp null phenotypes with the characterized Mmp inhibitor minocycline (Dziembowska et al, 2013;Siller and Broadie, 2012), we show that mutant defects are causally linked to Mmp hyperactivity (Fig. 6).…”

“…In particular, the BMP ligand Gbb gates synapse growth and neurotransmission strength in response to closely regulated contextual cues (Piccioli and Littleton, 2014). Within the canonical pathway, secreted Gbb ligand drives the phosphorylation of MAD ( pMAD) locally within the NMJ terminal, which then relays a signal for pMAD to enter distant motor neuron nuclei in the ventral nerve cord (VNC) (McCabe et al, 2003;Smith et al, 2012). We first tested extracellular Gbb ligand levels in the NMJ synaptomatrix of the genetic background control (w…”

Assessment of Biometal Profile in Children with Autism Spectrum Disorder, with Attention Deficit Hyperactivity Disorder, or with Other Psychiatric Diagnoses: A Comparative Outpatient Study

“…There are also some observations from patients with fragile X syndrome suggesting that interactions between zinc and glutamate may exist [32]. It is conceivable that zinc after being absorbed by the postsynaptic neuron can act as an important trophic factor, i.e.…”