Endosomal-Lysosomal Dysfunction in Neurodegenerative Diseases

The endosomal-lysosomal system underpins essential neuronal functions by coordinating the uptake, sorting and degradation of proteins and organelles. Early endosomes receive internalised cargo, maturing through a network of membrane-bound compartments into late endosomes and lysosomes, where acid-dependent hydrolases effect proteolysis. Autophagy converges on this system, delivering larger substrates via autophagosomes for lysosomal clearance. Defects in any step—from endocytic sorting to lysosomal acidification—disrupt proteostasis, leading to accumulation of misfolded proteins such as amyloid-β, α-synuclein and TDP-43. Genetic risk factors, including mutations in key sorting regulators and components of the vacuolar-type ATPase proton pump, further compromise organelle homeostasis. Emerging evidence indicates that impaired lysosomal repair mechanisms amplify inflammatory signalling and trigger neuronal death. Such dysfunction is observed across Alzheimer’s, Parkinson’s and frontotemporal dementias, often preceding clinical symptoms. Restoring endolysosomal fidelity offers a unifying strategy to arrest protein aggregation, attenuate neuroinflammation and preserve synaptic integrity.

Research from Nature Portfolio

Recent studies have revealed that ageing neurons exhibit intrinsic declines in lysosomal repair capacity and proteostasis, exacerbated in disease-relevant models. In a human neuron model retaining age-associated characteristics, deficits in lysosomal membrane integrity and ESCRT-mediated repair were linked to increased inflammatory cytokine release and cell death. Pharmacological enhancement of lysosomal function reduced accumulation of pathogenic proteins and dampened neuroinflammation, underscoring lysosomal homeostasis as an early intervention target. Complementary work in multiple mouse models of Alzheimer’s disease has uncovered a distinctive autophagic-lysosomal failure pattern termed PANTHOS, in which defective acidification within autolysosomes leads to intraluminal amyloid fibril formation. Neurons exhibiting this phenomenon were shown to be principal sources of extracellular plaques. These insights converge on lysosomal acidification and repair as central to neurodegenerative cascade initiation and progression.

Endosomal-Lysosomal Dysfunction in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in endosomal-lysosomal dysfunction in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Endosome: A membranous compartment that internalises and sorts cell surface and extracellular material.

Lysosome: An acidic organelle containing hydrolases that degrades proteins, lipids and organelles.

Autophagy: A catabolic process whereby cytoplasmic material is sequestered in autophagosomes for lysosomal degradation.

ESCRT (endosomal sorting complex required for transport): A set of protein complexes that mediate membrane remodelling and repair.

Vacuolar-type ATPase (v-ATPase): A proton pump responsible for acidifying endosomes and lysosomes, essential for enzymatic activity.

Proteostasis: The cellular network that regulates protein synthesis, folding, trafficking and clearance.

References

1. The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration. Translational Neurodegeneration (2015).
2. Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases. Translational Neurodegeneration (2023).
3. Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer’s disease. Nature Cell Biology (2025).
4. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nature Neuroscience (2022).
5. APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer’s disease. Brain (2024).