NEUROLOGICAL DISEASE

Many neurological diseases arise from malfunction of spines or synapses. We study synapse modification and function as it relates to two such diseases, Alzheimer’s Disease and Amyotrophic Lateral Sclerosis (ALS; Lou Gherig’s Disease).
            Alzheimer’s Disease: Alzheimer’s Disease is a neurodegenerative disease characterized by cognitive decline and neuron death. Familial cases of Alzheimer’s Disease arise from mutations in Presenilin-1, a component of the specialized intra membrane cleavage protease, gamma-secretase, and from mutations in Amyloid Precursor Protein (APP), a gamma secretase substrate. Our work shows that gamma secretase is found at synapses of hippocampal neurons, where it cleaves numerous substrates involved in synapse function and maturation. Our work indicates that gamma secretase cooperates at synapses with membrane type matrix metalloproteinases (Restituito, et al, in preparation, Monea et al., 2006 (PDF)) in cleaving synaptic substrates, including the cadherins. We are studying the control of gamma secretase function by synaptic activity and its possible role in synapse modification and signaling. (Figure)
            Amyotrophic Lateral Sclerosis: Amyotrophic Lateral Sclerosis is a neurodegenerative disease involving the progressive loss of motor neurons. The cause of neuron death is not established but it has been reported that in ALS patients, the editing of the GluR2 AMPAR subunit mRNA fails.  Editing of GluR2 mRNA changes the amino acid residue at the apex of the GluR2 pore-forming hairpin from glutamine to arginine, which controls AMPAR assembly (Greger et al., 2002 (PDF), 2003 (PDF) 2006 (PDF)) and results in a block to the conductance of Ca²⁺ by GluR2-containing AMPA channels. We have shown that when editing fails, the resulting GluR2-Q subunit is highly toxic to neurons because it can traffick freely to synapses and also conduct Ca²⁺ ions, which are excitotoxic when in excess (Mahajan and Ziff, 2007). We are studying the basis for the Ca²⁺-dependent GluR2 excitotoxicity and the mechanisms that impair GluR2 editing.

1. AMPA RECEPTOR TRAFFICKING AND THE CONTROL OF SYNAPSE STRENGTH.

2. SPINE AND SYNAPSE MORPHOGENESIS

3. NEUROLOGICAL DISEASE