Unifying biology of neurodegeneration in lysosomal storage diseases

Ludlaim, Anna M, Waddington, Simon N ORCID: https://orcid.org/0000-0003-4970-4730 and McKay, Tristan R ORCID: https://orcid.org/0000-0002-9128-9115 (2025) Unifying biology of neurodegeneration in lysosomal storage diseases. Journal of Inherited Metabolic Disease, 48 (1). e12833. ISSN 0141-8955

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Abstract

There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single‐gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.