Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder typically resulting from biallelic loss-of-function variants in the ARSA gene which encodes the lysosomal enzyme, arylsulphatase A, leading to the accumulation of its substrate, sulphatide, and widespread demyelination. Although gene therapy is available for MLD, it is limited by high cost and a narrow window for intervention, which means the development of therapies for MLD remains a key goal. The aim of the present study was to explore disease mechanisms in MLD with a view to identifying novel targets for therapeutic intervention for patients who cannot avail of gene therapy. Postmortem globus pallidus and dentate nucleus tissue was obtained from MLD cases (N=5; age 2-33 years old) and compared to age-, sex and ethnicity matched controls (N=5) and studied using discovery proteomics which demonstrated a marked inflammatory response, activation of the mTOR pathway, oxidative stress and metabolic remodelling in MLD cases. Histological analysis of inflammatory markers, including the terminal fragment of complement pathway activation, C3d, and the secreted glycoprotein YKL-40, a commonly used biomarker for inflammation, demonstrated their enrichment in MLD cases. Given that the mTOR pathway plays a key role in supressing autophagy, we next investigated autophagy and identified the accumulation of autophagosomes in MLD cases, consistent with deficient autophagy. Taken together, these findings suggest inflammation and autophagy dysfunction are key processes involved in MLD and that the mTOR pathway could be a novel therapeutic target for MLD.