LAUSR

Simple Summary Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons in the brain and spinal cord. Mutations in the gene Matr3 have been linked to ALS, including the autosomal dominant missense mutation S85C. We previously created a mouse model containing the S85C mutation in the Matr3 gene to understand how it causes ALS. The S85C mice exhibited MATR3 staining loss in selective populations of degenerating neurons, such as Purkinje cells in the cerebellum and α-motor neurons in the lumbar spinal cord. However, studies have shown that neurons other than motor neurons may be involved in contributing to ALS; therefore, we investigated additional neuronal cell types in the spinal cord and brain. Here, we found that MATR3 staining is selectively reduced in interneurons and α-motor neurons of the cervical and thoracic regions of the spinal cord, as well as in subsets of upper motor neurons and hippocampal neurons. These neurons did not exhibit cell body loss; however, how the MATR3 loss affects neuronal function remains to be determined. Overall, these findings demonstrate that the MATR3 S85C mutation affects other neuronal types of the brain and spinal cord in addition to motor neurons, suggesting that these additional neuronal types are involved in ALS pathogenesis. Abstract The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.