Lysosome trafficking and signaling in health and neurodegenerative diseases

Abstract

Lysosomes, single-membrane organelles defined by a uniquely strong acidic lumenal pH and high content of acid hydrolases, are the shared degradative compartments of the endocytic and autophagic pathways. These pathways, and especially lysosomes, are points of particular vulnerability in many neurodegenerative diseases. Beyond the role of lysosomes in substrate degradation, new findings have ascribed to lysosomes the leading role in sensing and responding to cellular nutrients, growth factors and cellular stress. This review aims to integrate recent concepts of basic lysosome biology and pathobiology as a basis for understanding neurodegenerative disease pathogenesis. Here, we discuss the newly recognized signaling functions of lysosomes and specific aspects of lysosome biology in neurons while re-visiting the classical defining criteria for lysosomes and the importance of preserving strict definitions. Our discussion emphasizes dynein-mediated axonal transport of maturing degradative organelles, with further consideration of their roles in synaptic function. We finally examine how distinctive underlying disturbances of lysosomes in various neurodegenerative diseases result in unique patterns of auto/endolysosomal mistrafficking. The rapidly emerging understanding of lysosomal trafficking and disruptions in lysosome signaling is providing valuable clues to new targets for disease-modifying therapies.

Keywords: Autophagy; Axonal transport; Dynein; Lysosomal signaling; Lysosome; Lysosome positioning; Neurodegenerative disease; Nutrient-sensing.

Fig. 1.. Lysosome signaling in anabolic and catabolic states.

Anabolic signaling is favored by nutrient replete conditions (upper panel). mTORC1 is recruited to the lysosomal surface by the vATPase-SLC38A9-Ragulator-Rag GTPase complex, which senses amino acids and cholesterol levels within lysosomes. mTORC1, the master growth regulator, is activated by Rheb GTPase that is also present on the lysosomal surface and is activated by growth factor signals from the cell surface. mTORC1 phosphorylates TFEB, which is then sequestered in the cytoplasm. The interaction between Ragulator and BORC is weak, which facilitates kinesin recruitment by Arl8 and its effector SKIP. Kinesin is also recruited by Rab7 and its effector FYCO. Kinesin-mediated centrifugal transport of lysosomes to the cell periphery promotes mTORC1 activation by growth factor signaling on the cell surface. Both TRPML1-mediated Ca²⁺ release and the ATP-sensitive TPC-mediated Na⁺-release are inhibited under well fed conditions. Conversely, catabolic signaling is favored by nutrient depletion (lower panel). mTORC1 is released from vATPase-SLC38A9-Ragulator-Rag GTPase complex. The mTORC1 activator, Rheb GTPase, is inhibited in the absence of growth factor signaling. Inactivated mTORC1 is no longer able to phosphorylation TFEB. Ragulator instead interacts with AXIN and AMPK that promote catabolic signaling. Interaction strengthens between Ragulator and BORC, inhibiting kinesin recruitment. PI (3,5)P₂-mediated activation of TRPML1 channel triggers lysosomal Ca²⁺ efflux, activating CaN, which in turn dephosphorylates TFEB and stimulates its nuclear trans-location. Nuclear TFEB activates CLEAR gene transcription for lysosome biogenesis. TRPML1 activity also promotes dynein-mediated centripetal transport of lysosomes via the calcium-sensing protein ALG2. Perinuclear localization of lysosomes facilitates the delivery of nascent lysosomal constituent from the Golgi, thereby promoting lysosomal degradative function. Under low level of ATP, TPC-mediated Na⁺ release affects the lysosomal membrane potential in a manner that helps maintaining vATPase proton pumping activity during starvation.

Fig. 2.. Neurodegenerative diseases disrupt retrograde axonal transport of maturing degradative organelles in lysosomal pathways.

This schematic highlights disease-linked gene mutations or pathogenic factors implicated in the impairment of motor-cargo association or motor activity. Mutations of many additional genes alter organelle function and structure, including abnormal enlargement in vesicle size (refer to (Nixon, 2016)), contributing to transport deficits or to other deficits of endosomal-lysosomal function or autophagy. Upper left panel shows the progressive acidification of degradative organelles as they are transported retrogradely from the distal to the proximal axon, becoming fully acidified in the cell body. Boxed areas are enlarged in bottom and right panels. (A) Early endosomes mature into late endosomes in a process that involves the conversion of Rab5 into Rab7 associated on endosomal membranes. Late endosomes fuse with double-membraned autophagosomes to form amphisomes. Dynein and dynactin are recruited to late endosomes or amphisomes. Dynein is recruited via interaction of dynein subunits DIC or LIC with various adaptors, which is competitively inhibited by aberrant interactions between dynein subunits and pathogenic peptides or proteins associated with AD, HD and ALS. Dynactin is recruited by Rab7 effectors to cholesterol-rich membrane domains and transferred to spectrin. (B) Retrograde transport is initiated in a process that requires the ordered recruitment of microtubule plus-end binding proteins (+TIPs) and the dynactin p150 CAP-Gly domain, as well as dynein interaction with LIS1/Nudel. p150 mutation within the CAP-Gly domain is associated with Perry syndrome. (C) Processive dynein-mediated retrograde movement is promoted by (i) clustering of multiple dynein motors within cholesterol-rich membrane domain, (ii) inhibition of kinesin by maintaining the dephosphorylated status of the adaptor JIP1, (iii) Nudel dephosphorylation, which is inhibited in ALS and (iv) maintenance of dephosphorylated status of DIC. Lysosomal deacidification results from loss of PSEN1 function in AD or other disease mechanisms, hyper-activating Ca²⁺ efflux and leading to aberrant DIC phosphorylation, which detrimentally impacts dynein activity.