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Brain research (1)
The Journal of biological chemistry (1)
Rothstein, Jeffrey D. (2)
Bartus, Raymond T. (1)
Bishop, Kathie M. (1)
Gasmi, Mehdi (1)
Haenggeli, Christine (1)
Lepore, Angelo C. (1)
Liu, Yiting (1)
Maier, Susanne (1)
Maragakis, Nicholas J. (1)
Ruggiero, Alicia M. (1)
Sitte, Harald H. (1)
Vidensky, Svetlana (1)
Year of Publication
Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS
Lepore, Angelo C.
Bishop, Kathie M.
Bartus, Raymond T.
Maragakis, Nicholas J.
The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.
Adeno; associated virus; insulin; like growth factor 1; gene therapy; neurodegeneration; amyotrophic lateral sclerosis; neuroprotection
Reticulon RTN2B Regulates Trafficking and Function of Neuronal Glutamate Transporter EAAC1*
Ruggiero, Alicia M.
Sitte, Harald H.
The Journal of biological chemistry
Excitatory amino acid transporters (EAATs) are the primary regulators of extracellular glutamate concentrations in the central nervous system. Their dysfunction may contribute to several neurological diseases. To date, five distinct mammalian glutamate transporters have been cloned. In brain, EAAC1 (excitatory amino acid carrier 1) is the primary neuronal glutamate transporter, localized on the perisynaptic membranes that are near release sites. Despite its potential importance in synaptic actions, little is known concerning the regulation of EAAC1 trafficking from the endoplasmic reticulum (ER) to the cell surface. Previously, we identified an EAAC1-associated protein, GTRAP3-18, an ER protein that prevents ER exit of EAAC1 when induced. Here we show that RTN2B, a member of the reticulon protein family that mainly localizes in the ER and ER exit sites interacts with EAAC1 and GTRAP3-18. EAAC1 and GTRAP3-18 bind to different regions of RTN2B. Each protein can separately and independently form complexes with EAAC1. RTN2B enhances ER exit and the cell surface composition of EAAC1 in heterologous cells. Expression of short interfering RNA-mediated knockdown of RTN2B decreases the EAAC1 protein level in neurons. Overall, our results suggest that RTN2B functions as a positive regulator in the delivery of EAAC1 from the ER to the cell surface. These studies indicate that transporter exit from the ER controlled by the interaction with its ER binding partner represents a critical regulatory step in glutamate transporter trafficking to the cell surface.
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