About this Research Topic
Autophagy is a phylogenetically conserved catabolic cellular pathway, by which toxic protein aggregates are cleared from the cytoplasm through autophagosomal engulfment, before being transported to lysosomes for degradation. A common factor in multiple neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyloid Lateral Sclerosis (ALS), is the pathological aggregation of misfolded amyloid beta, tau, huntingtin, alpha-synuclein, and DNA-binding protein 43 (TDP-43). Misfolded proteins exacerbate neuroinflammation and trigger neurons to release pro-inflammatory cytokines, which in turn activates the microglial autophagy pathway to clear these proteins. However, aging-associated changes in microglial gene expression can cause a reduction in the microglial response to misfolded protein aggregates. Changes in the microglial phenotype can also inhibit autophagy, increasing neuronal damage by prolonging their exposure to inflammatory mediators, which further activates the release of pro-inflammatory factors and ultimately triggers a neuroinflammatory cascade. The continued aggregation of toxic proteins and heightened neuroinflammatory state contributes to neuronal and microglial dystrophy, leading to neurodegenerative pathology.
Genes associated with different neurodegenerative diseases have been observed to impact autophagy along various points in its cellular pathway, including reduced expression or inhibition of proteins required for the formation of the autophagosome, impairment of autophagosome-lysosome fusion, and lysosomal alkalization, which prevents lysosomal proteases from degrading captured cargo. When toxic protein aggregates are continuously sequestered but remain undigested in autophagic organelles, the resulting increase in their physical size becomes another contributing factor to neuronal dysfunction and eventual neurodegeneration. Conversely, experimental induction of the autophagy-lysosomal pathway has been found to ameliorate neuropathology in cellular and nonhuman animal models of neurodegenerative disease. Taken together, these findings suggest that recovery of the autophagy-lysosomal pathway may constitute an effective therapeutic target for neurodegenerative diseases.
The primary objective of this Research Topic is to gain a deeper understanding of the impairment of the autophagy-lysosomal pathway in neurodegenerative diseases and to investigate pharmacological methods to restore its function. We welcome Original Research, Review, and Mini Review articles which focus on the following subtopics:
• Interaction between the autophagy-lysosomal pathway and beta amyloid, tau, huntingtin, alpha-synuclein, and DNA-binding protein 43 (TDP-43) aggregates.
• How the autophagy-lysosomal pathway is altered in neurodegenerative diseases, including but not limited to Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyloid Lateral Sclerosis (ALS).
• Promotion of toxic protein aggregate clearance via autophagy induction or alteration of proteins associated with the autophagy-lysosomal pathway.
• Pharmacological compounds to enhance autophagy in neurodegenerative diseases.
• Amelioration of lysosomal dysfunction in neurodegenerative diseases.
Genes associated with different neurodegenerative diseases have been observed to impact autophagy along various points in its cellular pathway, including reduced expression or inhibition of proteins required for the formation of the autophagosome, impairment of autophagosome-lysosome fusion, and lysosomal alkalization, which prevents lysosomal proteases from degrading captured cargo. When toxic protein aggregates are continuously sequestered but remain undigested in autophagic organelles, the resulting increase in their physical size becomes another contributing factor to neuronal dysfunction and eventual neurodegeneration. Conversely, experimental induction of the autophagy-lysosomal pathway has been found to ameliorate neuropathology in cellular and nonhuman animal models of neurodegenerative disease. Taken together, these findings suggest that recovery of the autophagy-lysosomal pathway may constitute an effective therapeutic target for neurodegenerative diseases.
The primary objective of this Research Topic is to gain a deeper understanding of the impairment of the autophagy-lysosomal pathway in neurodegenerative diseases and to investigate pharmacological methods to restore its function. We welcome Original Research, Review, and Mini Review articles which focus on the following subtopics:
• Interaction between the autophagy-lysosomal pathway and beta amyloid, tau, huntingtin, alpha-synuclein, and DNA-binding protein 43 (TDP-43) aggregates.
• How the autophagy-lysosomal pathway is altered in neurodegenerative diseases, including but not limited to Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyloid Lateral Sclerosis (ALS).
• Promotion of toxic protein aggregate clearance via autophagy induction or alteration of proteins associated with the autophagy-lysosomal pathway.
• Pharmacological compounds to enhance autophagy in neurodegenerative diseases.
• Amelioration of lysosomal dysfunction in neurodegenerative diseases.
Keywords: autophagy, lysosome, neurodegeneration, cellular catabolism, autophagosome, aging, protein aggregates, neurodegenerative diseases, Alzheimer's disease, Huntington's disease, Parkinson's disease, Amyloid Lateral Sclerosis, amyloid beta, tau, huntingtin, alpha-synuclein, DNA-binding protein 43, microglia
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
