Andrew Harris

Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness and degeneration of both upper and lower motor neuron symptoms.¹ Failure of the respiratory muscles often limits survival to 2-5 years after disease onset.¹ Currently, there is no definitive cure for ALS and medications are purely symptomatic.² ALS is a multifactorial disease with interactions between aging-related dysfunction, environmental factors, and genetic mutations.¹ The most common neuropathological signature of ALS is cytoplasmic aggregation of TDP-43 which is found in more than 95% of cases.¹ This protein plays a crucial role in regulating various aspects of RNA processing, and upon mislocalization from the nucleus to the cytoplasm, causes toxic protein aggregates that interfere with muscle trophic factors such as the androgen receptor (AR).^2,3 ALS is more prevalent in males and shows sex-specific differences which could indicate that sex hormones may be actively involved in the onset and progression of the disease.^1,4

Objective: In this narrative review, we explored how the loss or dysfunction of the AR within the nervous system may play a role in the pathogenesis of ALS.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2023 using the following keywords: “Amyotrophic Lateral Sclerosis”, “androgen”, “steroid hormones”, “modulation”.

Results: Studies using C2C12 myoblasts indicated that AR protein levels showed a time-dependent increase in the presence of dihydrotestosterone and a time-dependent reduction in response to cycloheximide (a known protein synthesis inhibitor in eukaryotic cells).⁴ The SOD1^G93A (superoxide dismutase) transgenic mouse model is frequently used in ALS preclinical research due to the sexually dimorphic differences displayed with males exhibiting consistently earlier disease onset. AR immunostaining using the SMI-32 neurofilament marker showed robust staining within the spinal motor neurons of wild-type mice and markedly less staining in SOD1^G93A males.⁴ Additionally, AR loss in motor neurons showed regional variation, with the most significant loss in the cervical and lumbar spinal cord and least degeneration in several of the cranial nerve nuclei.⁵ Normalization of testosterone in male Wobbler mice showed several neuroprotective effects including slowed progression of paw abnormalities and improved performance on rotarod.⁶ AR antagonism with flutamide accelerated disease onset and motor dysfunction in male SOD1^G93A mice compared to wild-type mice.⁷ Interestingly, neural AR deletion and global AR overexpression was not found to significantly alter disease course in SOD1^G93A generated AR^fl, NesCre^+/-, or nARKO genotypes, potentially confounded by hypometabolic phenotypes.⁸

Conclusions: The activation of androgen receptors using DHT or testosterone has been known to provide neuroprotective effects within the peripheral and central nervous systems. This along with the sexually dimorphic differences in ALS onset and presentation stands to reason that steroid hormones play a role in disease progression. There is evidence using the SOD1^G93A mouse model of ALS that modulation of androgen receptor expression can be therapeutic in the pathogenesis of ALS. The loss of AR is clearly implicated in the destruction of motor neurons, but the extent and regional variation of damage differs between neuronal cell lines. However, conflicting results seen with the AR^fl, NesCre^+/-, and nARKO genotypes as well as the lack of human clinical studies leave the association between the androgen receptor and ALS relatively fragile. Further research is needed to better establish this relationship and its potential uses in clinical practice.

Works Cited:

1. Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918-1929. doi:10.1111/ene.14393
2. Gupta D, Vagha S, Dhingra H, Shirsath H. Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review. Cureus. 2023;15(11):e48691. Published 2023 Nov 12. doi:10.7759/cureus.48691
3. Bianchi VE, Rizzi L, Bresciani E, Omeljaniuk RJ, Torsello A. Androgen Therapy in Neurodegenerative Diseases. J Endocr Soc. 2020;4(11):bvaa120. Published 2020 Aug 21. doi:10.1210/jendso/bvaa120
4. McLeod VM, Chiam MDF, Lau CL, Rupasinghe TW, Boon WC, Turner BJ. Dysregulation of Steroid Hormone Receptors in Motor Neurons and Glia Associates with Disease Progression in ALS Mice. Endocrinology. 2020;161(9):bqaa113. doi:10.1210/endocr/bqaa113
5. McLeod VM, Chiam MDF, Perera ND, Lau CL, Boon WC, Turner BJ. Mapping Motor Neuron Vulnerability in the Neuraxis of Male SOD1G93A Mice Reveals Widespread Loss of Androgen Receptor Occurring Early in Spinal Motor Neurons. Front Endocrinol (Lausanne). 2022;13:808479. Published 2022 Feb 22. doi:10.3389/fendo.2022.808479
6. Lara A, Esperante I, Meyer M, et al. Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2021;58(5):2088-2106. doi:10.1007/s12035-020-02209-5
7. McLeod VM, Lau CL, Chiam MDF, et al. Androgen receptor antagonism accelerates disease onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol. 2019;176(13):2111-2130. doi:10.1111/bph.14657
8. Tomas D, McLeod VM, Chiam MDF, Wanniarachchillage N, Boon WC, Turner BJ. Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis. Sci Rep. 2021;11(1):9255. Published 2021 Apr 29. doi:10.1038/s41598-021-88415-0