Interruption of Endolysosomal Trafficking After Focal Brain Ischemia

Abstract

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.

TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic‐ischemic brain injury

“…Lysosomes, usually terminal lysosomes, are critical members of the endolysosomal system that participate in the intracellular quality control mechanism, and are required for the efficient removal of damaged organelles (Langemeyer et al, 2018). The commonly used lysosomal marker, LAMP, is a major component of late endosomes and endolysosomes (Hu et al, 2021). Therefore, we used LAMP‐1 as a marker of the endolysosomal system.…”

Cathepsin B knockout confers significant brain protection in the mouse model of stroke

“…groups of structures: (i) late endosome (LE), (ii) endolysosome (EL), and (iii) "terminal" lysosome, hereafter referred to as lysosome (L). Each group of these structures undergoes a series of transitions from an early naive stage to a mature form (Hu et al, 2021). The LE receives newly synthesized lysosome structural proteins and digestive enzymes from Golgi apparatus as well as waste cargoes from both endocytic and autophagic pathways.…”

“…However, at its high intraluminal pH (6.0), LE's acidic hydrolases are mostly inactive and cannot degrade the waste cargoes. To process these cargoes, the LE must fuse with a more acidic L (pH 4.0-4.5) to form a hybrid EL (~pH 4.5) (Bright et al, 2016;de Araujo et al, 2020;Bissig et al, 2017;Hu et al, 2021).…”

“…The fusion between L and LE is mediated by several protein complexes. The core complex consists of: (i) N-ethylmaleimide sensitive factor ATPase (NSF), (ii) soluble NSF attachment protein (SNAP), and (iii) SNAP receptors (SNAREs) (Hu et al, 2021). Interactions between SNAREs from L and LE membranes facilitate the merging of these two organelles into a single EL.…”

“…After fusion, SNAREs on the EL membrane form an inactive stable cis-complex that must be dissociated or reactivated by NSF ATPase and its adaptor protein SNAP to convert the EL to a new L. This transitional process, from L-to-LE fusion and then the ELto-L conversion, is defined as a "endolysosomal cycle". This cycle is crucial for the removal of intracellular protein aggregates and damaged organelles (Hu et al, 2021). While there are >60 members of SNAREs and three members of SNAPs, there is only one member of NSF in mammalian cells (Hong and Lev, 2014;Yoon and Munson, 2018;Baker and Hughson, 2016).…”