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. 2023 Feb 22;146(5):1745–1757. doi: 10.1093/brain/awac470

Figure 4.

Figure 4

Future recommendations. (A) A large sample of C9ORF72-ALS patients should be studied using a validated questionnaire, such as the HAPAQ, to establish in a larger scale study whether strenuous PA exacerbates the clinical phenotype. This may allow lifestyle advice to be provided to at-risk family members with this genetic subtype of ALS. (B) Skin biopsies can be taken from participants with ALS and healthy controls. The fibroblasts can be reprogrammed to generate motor neurons, astrocytes and microglial cells. These human cell models can be studied to assess in detail pathophysiological changes when subjected to stresses e.g. hypoxia and oxidative stress, which operate during strenuous PA. The differences in stress response can be analysing using RNA sequencing, investigating any dysregulation of the response transcriptome in cell models of ALS compared to controls. (C) There are known transcriptomic changes present in PBMCs following strenuous exercise. The genetic factors predisposing to dysregulation of the physiological pathways can be analysed in large datasets of whole genome sequencing from a large sample of ALS patients. (D) Animal models of genetic subtypes of ALS beyond SOD1 can be studied to evaluate the effect of strenuous PA on disease parameters such as age of onset and survival. For example, for C9ORF72 ALS relevant Drosophila, zebrafish and mouse models have been generated, which will allow evaluation of this genetic–environmental interaction.97–100 Figure created using BioRender.com.