Exploration of the Pathogenesis of Amyotrophic Lateral Sclerosis from the Perspective of Motor Neuron TDP-43 Protein Expression and ADAR2 Activity

Amyotrophic lateral sclerosis (ALS) is a common adult-onset nervous system degenerative disease, characterized by the progressive loss of upper and lower motor neurons. TDP-43 pathology in motor neurons is a hallmark of ALS. In addition, the reduced expression of an RNA-editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), increases the expression of GluA2 at an unedited glutamine/arginine (Q/R) site in the motor neurons of patients with sporadic ALS. The change in the amino acid residue at the Q/R site of GluR2 results in marked alterations in channel properties of AMPA receptors, which increases Ca2+ permeability, and this increase in Ca2+ influx plays a key role in the death of motor neurons. ADAR2 mRNA is a target RNA for TDP-43, and TDP-43 plays a regulatory role in the expression of ADAR2. Recently, researchers have explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that enables gene delivery to a wide array of central neurons after peripheral administration and observed that the expression of exogenous ADAR2 in the central neurons effectively prevented progressive motor dysfunction. AAV9-ADAR2 rescued the motor neurons from death by normalizing TDP-43 expression. Therefore, this AAV9-mediated ADAR2 gene delivery may enable the development of a gene therapy for ALS. i 2014 S. Karger AG, Basel