Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis

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.

MATR3’s Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases

“…The relevance of this presymptomatic MATR3 loss in these neurons is still unclear and requires further study; however, the depletion of MATR3 has been previously shown to be toxic to cortical neurons in vitro [ 22 ], suggesting that MATR3 loss may contribute to Purkinje cell loss and motor function defects. Further characterization of MATR3 S85C knock-in mice extended the population of neurons that display MATR3 loss to include the alpha motor neurons and interneurons in the cervical and thoracic spinal cord, and a subset of upper motor neurons and hippocampal CA1 neurons in the brain [ 95 ], without being associated with cell body loss. These results suggest that the S85C mutation affects selective neuronal populations in other regions of the brain in addition to motor-controlling neurons, which requires further investigation.…”

Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS

“…We have previously shown that Matr3 S85C/S85C mice exhibit Purkinje cell loss, defects in lower motor neurons, and increased microglial responses 29,30 . Therefore, we performed immunohistochemistry to assess whether knockout of Dectin-1 affects these neuropathological phenotypes.…”

“…To investigate the impact of the S85C mutation in MATR3 , we have previously generated a MATR3 S85C knock-in mouse line ( Matr3 S85C/S85C ) 29 . We have previously demonstrated that Matr3 S85C/S85C mice recapitulate ALS-like features, including a shortened lifespan, motor deficits, loss of Purkinje cells in the cerebellum, degeneration of lower motor neurons in the spinal cord, and microglial responses 29,30 . We have shown from RNA-sequencing data that Clec7a was the topmost upregulated gene in the cerebellum and lumbar spinal cord of these mutant mice 29 .…”

RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis

“…However, using the connectome, which indicates trans-synaptic pathways where interneurons are important, the propagation could be accomplished through either continuous or discontinuous spread ( Hossaini et al, 2011 ; Kanouchi et al, 2012 ; de Carvalho et al, 2014 ) as in work by You et al (2022) where the PV positive interneurons and alpha MNs are lost in the model of ALS.…”