Lysosomal dysfunction in neurodegeneration: emerging concepts and methods

Abstract

The understanding of lysosomes has come a long way since the initial discovery of their role in degrading cellular waste. The lysosome is now recognized as a highly dynamic organelle positioned at the crossroads of cell signaling, transcription, and metabolism. Underscoring its importance is the observation that, in addition to rare monogenic lysosomal storage disorders, genes regulating lysosomal function are implicated in common sporadic neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Developing therapies for these disorders is particularly challenging, largely due to gaps in knowledge of the underlying molecular and cellular processes. In this review, we discuss technological advances that have propelled deeper understanding of the lysosome in neurodegeneration, from elucidating the functions of lysosome-related disease risk variants at the level of the organelle, cell, and tissue, to the development of disease-specific biological models that recapitulate disease manifestations. Finally, we identify key questions to be addressed to successfully bridge the gap to the clinic.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; frontotemporal dementia; lysosomes.

Figure 1:. Genes implicated in lysosomal function and lysosomal processes are at the crossroads of several neurodegenerative diseases

Risk variants in lysosomal genes have been identified in several neurodegenerative diseases, including AD, PD, ALS and FTD. The implicated genes are involved in a broad range of lysosome-related pathways, such as acidification, endocytosis, autophagy, mitophagy and ER-golgi-lysosome trafficking. The risk variants may mediate their pathogenicity in/through various cell types, including neurons, microglia and astrocytes. Epigenetic pathways and systemic factors likely modulate the risk of these variants for the disease and thus contribute to the heterogeneity in disease progression.

Figure 2:. Blueprint for a better understanding of lysosomal dysfunction across neurodegenerative disorders

In-depth analysis of lysosomal roles in neurodegenerative diseases such as AD, PD,ALS, FTD and LSDs should include the following approaches: 1. Studying lysosomes in physiology and disease at the subcellular resolution, 2. Assessing the impact of lysosomal disease risk variants on non-neuronal cells and its relation to pathology, 3. Screening for genetic modifiers of disease risk conferred by lysosomal variants, and 4. Next-generation translational research involving analysis of genotype-specific post-mortem brains from patients. Such an approach will help identify disease-relevant mechanisms that can be investigated for development of novel disease-modifying therapies. Illustrations of human brain and DNA double-helix were exported from BioRender.com.