Abstract
Sex steroid hormones have been implicated as disease modifiers in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Androgens, signalling via the androgen receptor (AR), predominate in males, and have widespread actions in the periphery and the central nervous system (CNS). AR translocates to the cell nucleus when activated upon binding androgens, whereby it regulates transcription of target genes via the classical genomic signalling pathway. We previously reported that AR protein is decreased in the lumbar spinal cord tissue of symptomatic male SOD1G93A mice. Here, we further explored the changes in AR within motor neurons (MN) of the CNS, assessing their nuclear AR content and propensity to degenerate by endstage disease in male SOD1G93A mice. We observed that almost all motor neuron populations had undergone significant loss in nuclear AR in SOD1G93A mice. Interestingly, loss of nuclear AR was evident in lumbar spinal MNs as early as the pre-symptomatic age of 60 days. Several MN populations with high AR content were identified which did not degenerate in SOD1G93A mice. These included the brainstem ambiguus and vagus nuclei, and the sexually dimorphic spinal MNs: cremaster, dorsolateral nucleus (DLN) and spinal nucleus of bulbocavernosus (SNB). In conclusion, we demonstrate that AR loss directly associates with MN vulnerability and disease progression in the SOD1G93A mouse model of ALS.
Highlights
Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder characterised by the loss of motor neurons (MNs) [1]
androgen receptor (AR) was highly expressed in the nuclei of almost all layer V pyramidal neuron (LVPN) of WT mice (Figure 1H; Table 1), with SOD1G93A males displaying a reduction in LVPNs with detectable nuclear AR staining (94% vs. 73% for WT and SOD1G93A mice, respectively; Figure 1I)
With AR expression noticeably diminished throughout MNs of the central nervous system (CNS), we further explored this loss within the vulnerable MNs of the lumbar spinal cord over the disease course in male SOD1G93A mice
Summary
Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disorder characterised by the loss of motor neurons (MNs) [1]. ALS is defined by the loss of both upper and lower motor neurons. Glutamatergic upper motor neurons (UMN), referred to as corticospinal motor neurons (CSMNs), have cell bodies located in layer V of motor cortex. In humans, these large projection neurons are known as Betz cells, forming monosynaptic connections directly on lower motor neurons (LMN) in the brainstem and spinal cord. Cholinergic LMNs have cell bodies located in discrete brainstem clusters, known as cranial nerve (CN) nuclei, and throughout the spinal cord ventral horn, known as spinal MNs
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