The endolysosomal pathway and ALS/FTD

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered to be part of a disease spectrum that is associated with causative mutations and risk variants in a wide range of genes. Mounting evidence indicates that several of these genes are linked to the endolysosomal system, highlighting the importance of this pathway in ALS/FTD. Although many studies have focused on how disruption of this pathway impacts on autophagy, recent findings reveal that this may not be the whole picture: specifically, disrupting autophagy may not be sufficient to induce disease, whereas disrupting the endolysosomal system could represent a crucial pathogenic driver. In this review we discuss the connections between ALS/FTD and the endolysosomal system, including a breakdown of how disease-associated genes are implicated in this pathway. We also explore the potential downstream consequences of disrupting endolysosomal activity in the brain, outside of an effect on autophagy.

Keywords: C9ORF72; TDP-43; TMEM106B; autophagy; neurodegeneration; proteinopathy.

Figure 1:. A brief overview of the endo-lysosomal pathway.

After endocytosis, cargo is shuttled into the early endosome, which is marked by Rab5 and EEA1. From here, vesicles can be recycled back to the plasma membrane or can undergo maturation to become a late endosome, as marked by Rab7 and PI(3,5)P₂. During this maturation process, the endosome accumulates intraluminal vesicles (ILVs) through a process regulated by ESCRT complexes. It also takes in vesicles from the trans-Golgi network which can contain MPR-linked lysosomal enzymes and hydrolases. The resultant structure is called a multivesicular body (MVB). After depositing their cargo, MPRs are shuttled backed to the trans-Golgi network through a retrograde transport pathway mediated by the retromer. Late endosomes can fuse with lysosomes to become endolysosomes and degrade cargo. Both MVBs and endolysosomes can also fuse with autophagosomes en route to the autophagic degradation of cargo. Finally, endolysosomes can condense down to become lysosomes. LAMPs, like LAMP1 and LAMP2, are transmembrane glycoproteins that populate both late endosomes and lysosomes.

Figure 2:. Several ALS/FTD-related genes and risk factors have been implicated in the endo-lysosomal pathway.

VCP and alsin are implicated in endocytosis and the conversion of recycling endosomes into early endosomes, respectively. Alsin is also a regulator of Rab5 at the early endosome, where C9ORF72 and VCP also localize. TBK1 regulates Rab7 and endosome maturation, a process that is also dependent upon phosphoinositide conversions governed by FIG4 in complex with PIKfyve. Several factors are associated with late endosomes and MVBs, including proteins involved in the sorting of cargo into ILVs, like VCP and the ESCRT factor CHMP2B, and proteins linked to retromer function and retrograde transport, like C9ORF72, TBK1, and VAPB. At lysosomes, UBQLN2 regulates vacuolar ATPase (V-ATPase) levels, PGRN regulates lysosomal function and hydrolase activity, and C9ORF72 regulates mTOR and TFEB signaling. TMEM106B, an FTD risk factor, forms fibrils in diseased and aged brains, potentially inside the lysosome. TBK1, VCP and spatacsin are implicated in endosome and lysosome clearance and renewal. Under disease conditions (right), some factors are lost to haploinsufficiency and others are mutated, often resulting in impaired activity. TDP-43 often aggregates. In c9ALS/FTD, TBK1 is sequestered by poly(GA). These diverse defects can disrupt endo-lysosomal flux, stalling the pathway and resulting in the accumulation of enlarged endosomes and changes in lysosomal morphology and number. Of note, specific mutations and types of protein loss are unique to different familial conditions.