Neurodegenerative lysosomal disorders: A continuum from development to late age

Abstract

Neuronal survival requires continuous lysosomal turnover of cellular constituents delivered by autophagy and endocytosis. Primary lysosomal dysfunction in inherited congenital "lysosomal storage" disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of inherited adult-onset neurodegenerative diseases caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic pathways has grown considerably. In this Perspective, we classify a group of neurodegenerative diseases across the lifespan as disorders of lysosomal function, which feature extensive autophagic-endocytic-lysosomal neuropathology and may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. We highlight Alzheimer's disease as a disease within this group and discuss how each of the genes and other risk factors promoting this disease contribute to progressive lysosomal dysfunction and neuronal cell death.

Organellar Dysfunction in the Pathogenesis of Pancreatitis

“…Indeed, trypsinogen activation has been recently reported (78) in endocytic vacuoles in response to CCK hyperstimulation of acinar cells. A number of characteristics of pancreatitis are similar to those observed in lysosomal disorders (which are mostly caused by mutations that inactivate lysosomal hydrolases or affect their delivery to lysosomes)-such as block of autophagy, impaired maturation of cathepsins, decreased protein degradation, cell vacuolation and death, and the inflammatory response (59). Thus, our findings indicate that acute pancreatitis has features of a lysosomal disease, which should be taken into consideration in designing strategies to treat or mitigate pancreatitis.…”

“…Physiological autophagy triggers efficient turnover of autophagosomes into autolysosomes and stimulates protein degradation. Many diseases are associated with impaired autophagic flux, which is manifest, first of all, by vacuole accumulation (47,59). Impairment or retardation of the autophagic flux could be caused by a defective fusion of autophagosomes with lysosomes or by inefficient degradation of cellular constituents in autolysosomes (Fig.…”

“…Impairment or retardation of the autophagic flux could be caused by a defective fusion of autophagosomes with lysosomes or by inefficient degradation of cellular constituents in autolysosomes (Fig. 6) that may result from defective cathepsin activities (47,59).…”

Systems biology of the autophagy-lysosomal pathway

“…Aging brains exhibit reduced lysosomal function and, in neurodegenerative diseases, increased accumulation of macroautophagic vesicles has been observed in postmortem patient brains compared to normal controls. [4][5][6][7] Because of the importance of macroautophagy and lysosomal activities to cellular functions, it is expected that the two…”

Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy

“…Macroautophagy (hereafter, autophagy) has been implicated in bulk degradation of pathologic aggregates, such as the polyglutamine-expanded huntingtin inclusions observed in Huntington disease (13). ALP is a vital cellular process, and impairment of the ALP can lead to neurodegeneration, as demonstrated in animal models that are deficient in genes coding for autophagy proteins in neuronal tissue (14,15) and in human neurodegenerative lysosomal storage diseases (16,17).…”