Abstract
Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is pronounced cellular event in motor neurons diseases, such as amyotrophic lateral sclerosis (ALS). Genetic mutations contribute to only about ten percent of ALS. Thus understanding the involvement of other factors, such as epigenetic controls, is immensely valuable. Here, we investigated epigenomic signature of CSMN that become diseased due to misfolded SOD1 toxicity and TDP-43 pathology, by performing quantitative analysis of 5-methylcytosine (5mC) and 5-hydroxymethycytosine (5hmC) expression profiles during end-stage of the disease in hSOD1G93A, and prpTDP-43A315T mice. Our analysis revealed that expression of 5mC was specifically reduced in CSMN of both hSOD1G93A and prpTDP-43A315T mice. However, 5hmC expression was increased in the CSMN that becomes diseased due to misfolded SOD1 and decreased in CSMN that degenerates due to TDP-43 pathology. These results suggest the presence of a distinct difference between different underlying causes. These differential epigenetic events might modulate the expression profiles of select genes, and ultimately contribute to the different paths that lead to CSMN vulnerability in ALS.
Highlights
Corticospinal motor neurons (CSMN) are a unique population of motor neurons that are important for motor function
Using hSOD1G93A and prpTDP-43A315T mouse models of amyotrophic lateral sclerosis (ALS), which represent disease mechanisms that occur due to misfolded SOD1 toxicity and TDP-43 pathology, respectively, here, we reveal that CSMN based on the underlying cause of the disease display a distinct pattern of methylation and hydroxymethylation
We find that CSMN that are diseased due to mSOD1 toxicity, and TDP-43 pathology have distinct pattern of DNA
Summary
Corticospinal motor neurons (CSMN) are a unique population of motor neurons that are important for motor function These neurons collect and integrate inputs from other neurons in the brain, and relay that information to their spinal cord targets, maintaining a functional motor neuron circuitry [1]. Degeneration of CSMN results in motor neuron diseases such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS) [2]. ALS is a complex and heterogeneous disease that is manifested by progressive degeneration of CSMN, and spinal motor neurons [3]. Detection of CSMN loss is beginning to emerge as an early diagnostic marker of ALS [6], and improving CSMN health proved to be beneficial for the health and integrity of motor neuron circuitry [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
