The strongest case for this idea comes from genetics. Over the past twenty years, researchers hunting for genes that cause or raise the risk of neurodegenerative disorders have repeatedly landed on the endolysosomal system, the network of vesicles and organelles that ferries cargo to lysosomes for destruction. In Parkinson disease, the evidence is particularly compelling. A substantial proportion of genes linked to the condition encode proteins that are essential for lysosomal health, and the two most common genetic causes of Parkinson disease, mutations in GBA1 and LRRK2, both converge on lysosomal biology. Remarkably, both of these pathways are now being targeted in clinical trials, marking one of the first times that fundamental cell biology has been translated so directly into therapeutic strategies for a neurodegenerative illness.

The GBA1 story illustrates how a single gene can illuminate an entire disease mechanism. GBA1 encodes glucocerebrosidase, a lysosomal enzyme that breaks down fatty substances called glucosylceramides. People who carry one mutated copy of the gene are at markedly elevated risk of developing Parkinson disease, and studies have shown that reduced glucocerebrosidase activity in the substantia nigra, the brain region that degenerates in Parkinson disease, is associated with increased levels of alpha-synuclein, the protein that clumps into the Lewy bodies that define the disorder. Work from the Krainc laboratory and others has revealed a bidirectional loop: deficient glucocerebrosidase impairs the degradation of alpha-synuclein, while accumulating alpha-synuclein in turn blocks the delivery of fresh glucocerebrosidase to lysosomes, creating a vicious cycle of worsening protein aggregation and deepening lysosomal failure.

LRRK2, the other major Parkinson gene, tells a complementary story. This large kinase enzyme phosphorylates a family of Rab GTPases that regulate membrane trafficking throughout the cell. When lysosomes are damaged, LRRK2 is recruited to their surface through pathways involving the CASM machinery and GABARAP proteins, where it helps coordinate membrane repair and the removal of damaged lysosomal material. Pathogenic LRRK2 mutations boost kinase activity, producing enlarged lysosomes with reduced degradative capacity and impairing the clearance of alpha-synuclein. Because LRRK2 is also active in immune cells, its dysfunction extends to microglia, the brain’s resident immune cells, linking lysosomal failure to the neuroinflammation that accompanies neurodegeneration. LRRK2 kinase inhibitors, including the molecule BIIB122, have already been tested in patients, and a broad initiative called the LRRK2 investigative therapeutics exchange is working to overcome the remaining obstacles to translating this biology into disease-modifying therapies.

Beyond these headline genes, the review catalogues an expanding roster of lysosomal proteins implicated in Parkinson disease. Mutations in VPS35, a core component of the retromer complex that sorts cargo through endosomes, cause familial Parkinson disease and disrupt the retrieval of the chaperone-mediated autophagy receptor LAMP2A, which neurons use to deliver alpha-synuclein to lysosomes for destruction. ATP13A2, a lysosomal transporter whose loss causes an early-onset form of parkinsonism, exports polyamines from the lysosome, and its deficiency triggers lysosomal dysfunction and alpha-synuclein accumulation. The lysosomal ion channel TMEM175, identified through genome-wide association studies as a risk factor, regulates the proton balance that keeps lysosomes acidic enough for their digestive enzymes to function. Even the recently characterized Commander complex has emerged as a regulator of lysosomal function and Parkinson disease risk. Each of these discoveries reinforces the same message: many independent genetic insults funnel into a single vulnerable pathway.

In Alzheimer disease, the lysosomal connection takes a somewhat different form, centered on the endocytic trafficking machinery. Enlarged endosomes packed with amyloid-beta are among the earliest pathological changes detectable in neurons of people with Alzheimer disease, appearing before amyloid plaques form. The strongest genetic link is SORL1, which encodes the receptor SORLA, a key regulator of cargo trafficking through the endolysosomal system, including trafficking of the amyloid precursor protein. Loss-of-function variants in SORL1 substantially increase Alzheimer risk, and depletion of SORLA in human neurons impairs endosomal traffic even independently of amyloidogenic processing. Other risk genes, including BIN1, PICALM and CD2AP, all participate in endocytosis and endosomal sorting, and presenilin mutations that cause familial Alzheimer disease disrupt lysosomal acidification and autophagy, although the precise role of presenilins in this process remains debated.

The lipid-carrying protein APOE adds another layer to the Alzheimer picture. The APOE4 allele, the strongest common genetic risk factor for late-onset disease, promotes the accumulation of cholesterol in lysosomes of astrocytes, impairs mitochondrial function and dampens autophagy through multiple mechanisms, including direct binding of ApoE4 to gene regulatory elements that control autophagy genes. Meanwhile, TREM2, a receptor on microglia that depends on lysosomal processing for its function, shapes how immune cells respond to amyloid plaques, although a recent clinical trial targeting TREM2 failed, underscoring how much remains to be learned about translating lysosomal biology into treatments.

Frontotemporal dementia and amyotrophic lateral sclerosis, two clinically distinct disorders with heavily overlapping genetics, supply perhaps the most direct evidence that autophagy, the cellular self-eating process that delivers cargo to lysosomes, is essential for neuronal survival. Multiple ALS and FTD genes encode proteins that regulate autophagy at different steps: TBK1 and OPTN coordinate the selective removal of damaged mitochondria; VCP and UBQLN2 participate in extracting ubiquitinated proteins for degradation; SQSTM1, also known as p62, serves as a cargo receptor that tags aggregates for autophagic clearance; and C9ORF72, the most common genetic cause of both diseases, forms a complex that regulates Rab GTPases and mTORC1 signaling at the lysosome. Mutations in CHMP2B, part of the ESCRT-III machinery that repairs ruptured lysosomal membranes, cause a distinctive form of frontotemporal dementia characterized by lysosomal storage pathology, and recent work shows that the ALS-linked proteins annexin A11 and CHMP2B act sequentially in membrane repair.

Progranulin, encoded by the GRN gene, has become a focal point for therapeutic development in frontotemporal dementia. Haploinsufficiency, meaning that carriers of a single mutated GRN copy produce only half the normal amount of the protein, causes familial FTD and produces features resembling neuronal ceroid lipofuscinosis, a classic lysosomal storage disease. Progranulin supports lysosomal homeostasis through multiple mechanisms: it promotes lysosomal acidification, acts as a chaperone for the enzyme cathepsin D, facilitates the processing of prosaposin into saposins that activate lipid-degrading enzymes, and supports glucocerebrosidase activity. The risk gene TMEM106B, which regulates lysosomal size, motility and stress responses, modifies disease penetrance in GRN mutation carriers, and strikingly, TMEM106B itself was recently discovered to form amyloid fibrils in aged brains across multiple neurodegenerative diseases. Progranulin augmentation strategies, including an antibody called latozinemab that raises progranulin levels and AAV gene therapy, are already in clinical trials, with interim results reported for the gene therapy approach.

What emerges from this synthesis is a view of neurodegeneration as, at its core, a failure of cellular housekeeping that unfolds over decades. Neurons are uniquely vulnerable because they live as long as the organism, rely heavily on long-range transport of lysosomes along axons, and generate toxic metabolic byproducts such as oxidized dopamine that further damage lysosomes. The convergence of genetic evidence from four major disease families onto the endolysosomal system suggests that therapies aimed at restoring lysosomal health, whether by enhancing enzyme activity, improving acidification, boosting autophagic flux or repairing damaged lysosomal membranes, could offer benefits that span diagnostic boundaries. With GBA1 and LRRK2 trials underway in Parkinson disease, progranulin augmentation advancing in frontotemporal dementia and lysosome-targeting small molecules in preclinical development, the humble lysosome has moved from the margins of neuroscience to the center of the search for disease-modifying treatments.

Subject of Research: Lysosomal dysfunction as a mechanism of neurodegenerative disease

Article Title: Lysosomal dysfunction in neurodegenerative disease

Article References: Brooker, S. M., Coukos, R., & Krainc, D. (2026). Lysosomal dysfunction in neurodegenerative disease. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01262-3

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01262-3

Keywords: lysosome, neurodegeneration, Parkinson disease, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, GBA1, LRRK2, autophagy, progranulin, alpha-synuclein, endolysosomal trafficking