Endolysosomal and Autophagic Dysfunctions as Early Drivers of Neurodegeneration

Despite decades of research, the cause of degeneration of specific neuronal subsets in neurodegenerative conditions remains elusive. In both Alzheimer’s disease and Parkinson’s disease there are environmental and genetic factors that are associated with the risk of developing these diseases. Interestingly, most genetic risk factors of neurodegenerative diseases involve components of the autophagy-endolysosomal system. In several models of neurodegeneration there are morphological alterations in intermediates of the autophagy-endolysosomal pathway, including enlarged early endosomes and multivesicular bodies, as well as accumulation of unprocessed autolysosomes. The disturbance of the endolysosomal system alters the normal intracellular trafficking and organelle turnover. Recently, it has been proposed that alterations in the crosstalk between mitochondria, lysosomes and endosomes trigger early events of neurodegenerative processes.

Neurodegeneration is related to changes in the expression of endolysosomal proteins and lipid metabolism. Neurons with a reduced capacity of protein and organelle degradation are prone to accumulate toxic protein aggregates, which apparently are propagated through the release of extracellular vesicles. However, it is not well understood what causes the impairment of endolysosomal and autophagy pathways that may preclude protein aggregation and oxidative stress, events related to neurodegeneration. Several studies indicate that endosomal, lysosomal, and mitochondrial markers can be detected in extracellular vesicles derived from patients developing neurodegenerative diseases, and the levels of these markers can be used to discriminate between different neurological conditions.
There is a need for a better characterization of the temporal dynamics of endolysosomal and autophagic dysfunction, as this may help in the identification of novel cellular pathways related to neurodegeneration. Furthermore, we require a deeper understanding of the heterogeneity and organization of the endolysosomal compartments. This knowledge is essential to determine how alterations in the same pathway led to the different neurodegenerative diseases.

This Research Topic is focused on improving our understanding on how the alterations in organelle crosstalk triggers neurodegenerative processes. Specifically, the role of endolysosomal and autophagic dysfunction in the progression of neurodegenerative diseases including, but not limited to, Alzheimer’s, Parkinson’s, Huntington's disease, and ALS. The detailed analysis of endolysosomal and autophagy pathways may shed light on possible therapeutic strategies to halt the progression of neurodegenerative diseases.

We welcome original research and review articles covering, but not limited to, the following themes:

1. Identification and characterization of new genes and environmental factors associated with the endolysosomal and autophagy systems that promote neurodegeneration
2. In vivo and in vitro models addressing the cellular and molecular mechanisms of endolysosomal and autophagic dysfunction in neurodegeneration
3. Studies oriented to understanding how altered endolysosomal trafficking may result in a noxious molecular cargo in extracellular vesicles that contributes to the spread of toxic protein aggregates and the identification of novel biomarkers
4. Novel therapeutic (genetic or pharmaceutical) interventions targeting endolysosomal and autophagic systems as potential disease-modifying strategies

Topic Editor, Dr. Evandro F. Fang, has a CRADA arrangement with ChromaDex and is a consultant to Aladdin Healthcare Technologies and Vancouver Dementia Prevention Centre. The other Topic Editors declare no competition conflict of interest with regard to the Research Topic subject.