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Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1^G93A mice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1^G93A male mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1^G93A double transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1^G93A mice. In conclusion, the disease course of SOD1^G93A mice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.

SUBMITTER: Tomas D

PROVIDER: S-EPMC8085012 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.

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Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis.

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