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.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.
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