Autophagic and endo-lysosomal dysfunction in neurodegenerative disease

Abstract

Due to their post-mitotic state, metabolic demands and often large polarised morphology, the function and survival of neurons is dependent on an efficient cellular waste clearance system both for generation of materials for metabolic processes and removal of toxic components. It is not surprising therefore that deficits in protein clearance can tip the balance between neuronal health and death. Here we discuss how autophagy and lysosome-mediated degradation pathways are disrupted in several neurological disorders. Both genetic and cell biological evidence show the diversity and complexity of vesicular clearance dysregulation in cells, and together may ultimately suggest a unified mechanism for neuronal demise in degenerative conditions. Causative and risk-associated mutations in Alzheimer's disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease and others have given the field a unique mechanistic insight into protein clearance processes in neurons. Through their broad implication in neurodegenerative diseases, molecules involved in these genetic pathways, in particular those involved in autophagy, are emerging as appealing therapeutic targets for intervention in neurodegeneration.

Keywords: Autophagy; Endo-lysosome; Mitophagy; Neurodegeneration.

Fig. 1

Autophagy and endo-lysosomal mechanisms and related genes associated with neurodegenerative diseases. Macroautophagy begins with formation of an isolation membrane to engulf cargos selected for degradation. Elongation of the isolation membrane results in formation of the double membrane autophagosome marking the final step before lysosomal fusion and degradation. In parallel the endosomal system sorts molecules for either recycling or targeting to the lysosome, with chaperone-mediated autophagy (CMA) and microautophagy also delivering cargos to the lysosomes. Hydrolytic enzymes within the acidic lysosomal lumen digest the target and the constituents resulted from this are released into the cellular cytoplasm. Neurodegenerative disease causing or associated genes affecting various stages of autophagy are listed alongside the process in which they are involved. For additional information relating to disease association of listed genes, refer to Table 1

Fig. 2

Mitophagy and related genes associated with neurodegenerative diseases. Dysfunctional mitochondria are targeted for autophagic clearance by a number of specific adapters which are associated with neurodegenerative disorders. Upon depolarisation, PTEN-induced kinase 1 (PINK1) accumulates on the mitochondrial outer membrane (MOM), where it phosphorylates Ser65 of ubiquitin and the ubiquitin-like domain of PRKN. pS65-Ub acts as a positive-feedback mechanism for the further recruitment of PRKN to the MOM and activation of its E3 ubiquitin-ligase activity. PRKN ubiquitinates a number of targets on the MOM, including mitochondrial fusion proteins such as Mitofusin1 (MFN1), decorating the damaged organelle in poly-ubiquitin chains. F-Box Only Protein 7 (FBXO7) also participates in MFN1 ubiquitination. PINK1, PRKN and pS65-Ub chains on the MOM facilitates the recruitment of autophagy adapters Phosphotyrosine-Independent Ligand For The Lck SH2 Domain Of 62 KDa (p62), Nuclear Domain 10 Protein 52 (NDP52) and Optinuerin (OPTN). Parkinson’s disease-associated mutations in β-glucocerebrosidase (GBA) and Leucine Rich Repeat Kinase 2 (LRRK2) are considered to impair PRKN-mediated mitophagy. Phosphorylation of ALS-associated TBK1 in response to mitochondrial damage is dependent on NDP52 and OPTN recruitment, but subsequently increases the affinity of OPTN for poly-ubiquitin on the MOM. TBK1 also phosphorylates RAB7A, which in turn facilitates the recruitment / formation of ATG9 vesicles. The ULK1 complex and ATG9 vesicles are recruited / form de novo at damaged mitochondria and initiate autophagic engulfment. This is enhanced by the recruitment of LC3-II by p62. Neurodegenerative disease causing or associated genes affecting various stages of mitophagy are listed. For additional information relating to disease association of listed genes, refer to Table 1