Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

The endosomal network maintains cellular homeostasis by sorting, recycling and degrading endocytosed cargoes. Retromer organizes the endosomal sorting pathway in conjunction with various sorting nexin (SNX) proteins. The SNX27–retromer complex has recently been identified as a major endosomal hub that regulates endosome-to-plasma membrane recycling by preventing lysosomal entry of cargoes. Here, we show that SNX27 directly interacts with FAM21, which also binds retromer, within the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complex. This interaction is required for the precise localization of SNX27 at an endosomal subdomain as well as for recycling of SNX27-retromer cargoes. Furthermore, FAM21 prevents cargo transport to the Golgi apparatus by controlling levels of phosphatidylinositol 4-phosphate, which facilitates cargo dissociation at the Golgi. Together, our results demonstrate that the SNX27–retromer–WASH complex directs cargoes to the plasma membrane by blocking their transport to lysosomes and the Golgi.

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by memory decline and cognitive dysfunction. Although the primary causes of AD are not clear, it is widely accepted that the accumulation of amyloid beta (Aβ) and consecutive hyper-phosphorylation of tau, synaptic loss, oxidative stress and neuronal death might play a vital role in AD pathogenesis. Recently, it has been widely suggested that extracellular vesicles (EVs), which are released from virtually all cell types, are a mediator in regulating AD pathogenesis. Clinical evidence for the diagnostic performance of EV-associated biomarkers, particularly exosome biomarkers in the blood, is also emerging. In this review, we briefly introduce the biological function of EVs in the central nervous system and discuss the roles of EVs in AD pathogenesis. In particular, the roles of EVs associated with autophagy and lysosomal degradation systems in AD proteinopathy and in disease propagation are discussed. Next, we summarize candidates for biochemical AD biomarkers in EVs, including proteins and miRNAs. The accumulating data brings hope that the application of EVs will be helpful for early diagnostics and the identification of new therapeutic targets for AD. However, at the same time, there are several challenges in developing valid EV biomarkers. We highlight considerations for the development of AD biomarkers from circulating EVs, which includes the standardization of pre-analytical sources of variability, yield and purity of isolated EVs and quantification of EV biomarkers. The development of valid EV AD biomarkers may be facilitated by collaboration between investigators and the industry.

Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.