Understanding ALS Mechanism by Constructing and Analyzing Transgenic Mouse Models

Transgenic mouse models are an indispensable tool for understanding the mechanism of neurodegeneration in ALS research. Our lab constructs and analyzes transgenic mouse models for ALS in order to gain insights into the disease mechanism. We have constructed and analyzed several mouse models. First, we have analyzed mutant SOD1 mouse models by focusing the role of mitochondria in motor neurodegeneration. We revealed numerous functional and structural abnormalities in mitochondria in early stages of ALS, thus cementing the importance of mitochondrial damage in ALS disease progression (Xu et al., 2004). Second, we constructed a partial loss of TDP-43 function mouse model and demonstrated that these mice develop age-dependent motor neuron degeneration and paralysis, thereby suggesting that a loss of TDP-43 function can contribute to motor neuron degeneration and cause ALS (Yang et al., 2014). Third, we constructed a gain-of-function mouse model by overexpressing an ALS-associated mutant PFN1 gene. We have demonstrated that these mice develop age-dependent motor neuron degeneration and clinical symptoms of ALS (Yang et al., 2016) and have deposited these mice in Jackson Lab (Stock# 028608, 028607) so that they can be used by all ALS researchers. We are currently further analyzing the mechanism of neurodegeneration in these mice.