Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting upper and lower motor neurons in the central nervous system. Drugs like riluzole, edaravone, and tofersen treat disease symptoms or are designed for a specific pathological mutation (e.g., SOD1), but they cannot prevent or halt the disease. For this reason, the search for new therapeutic strategies continues. The voltage-gated calcium channel Ca V 2.2 might be a novel target in ALS treatment as the channel was shown to be overexpressed in murine SOD1*G93A cortical neurons, resulting in higher mortality. Further, murine SOD1*G93A motor neurons showed increased calcium currents mainly by an increased expression of the Ca V 2.2 channel. In addition, inhibition of the channel was hypothesized as mode of action for the all- d -enantiomeric peptide RD2RD2, a novel drug candidate for the treatment of ALS, which already demonstrated its efficacy in SOD1*G93A mice. To investigate the influence of the Ca V 2.2 channel on the progression of disease symptoms in the SOD1*G93A mouse model, a new double transgenic line was created, combining the ALS phenotype with a knockout of the Ca V 2.2 channel. The study showed that the Ca V 2.2 knockout on the SOD1*G93A background led to reduced SHIRPA and splay scores, and a delayed disease onset. Additionally, differences were detected between wildtype and single transgenic Ca V 2.2 KO mice. However, survival was not affected. Post mortem analysis of human tissue found more Ca V 2.2 in ALS cases in comparison to healthy control subjects confirming involvement of the channel in human ALS. These results indicate that the Ca V 2.2 calcium channel may play an influential role in early disease progression of ALS. • Creation of a novel double-transgenic mouse line combining the knockout of the Ca V 2.2 calcium channel and the SOD1*G93A mouse model of ALS. • Double-transgenic mice have less motoric deficits and a delayed disease onset. • First time to identify the Ca V 2.2 channel in human ALS samples.
Wintz et al. (Wed,) studied this question.