Search

Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels-an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive "inside-out" TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in PSEN1 knockout neurons. Our results, including features demonstrated in Alzheimer-mutant PSEN1 knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.

Lysosomal trafficking and maturation in neurons remain poorly understood and are unstudied in vivo despite high disease relevance. We generated neuron-specific transgenic mice to track vesicular CTSD acquisition, acidification, and traffic within the autophagic-lysosomal pathway in vivo, revealing that mature lysosomes are restricted from axons. Moreover, TGN-derived transport carriers (TCs), not lysosomes, supply lysosomal components to axonal organelles. Ultrastructurally distinctive TCs containing TGN and lysosomal markers enter axons, engaging autophagic vacuoles and late endosomes. This process is markedly upregulated in dystrophic axons of Alzheimer models. In cultured neurons, most axonal LAMP1 vesicles are weakly acidic TCs that shuttle lysosomal components bidirectionally, conferring limited degradative capability to retrograde organelles before they mature fully to lysosomes within perikarya. The minor LAMP1 subpopulation attaining robust acidification are retrograde Rab7 + endosomes/amphisomes, not lysosomes. Restricted lysosome entry into axons explains the unique lysosome distribution in neurons and their vulnerability toward neuritic dystrophy in disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The blood-testis barrier (BTB), similar to other blood-tissue barriers, such as the blood-brain barrier and the blood-retinal barrier, is used to protect the corresponding organ from harmful substances (e.g., xenobiotics) including drugs and foreign compounds. More importantly, the BTB allows postmeiotic spermatid development to take place in an immune privileged site at the adluminal (or apical) compartment to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. The BTB, however, also poses an obstacle in developing nonhormonal-based male contraceptives by sequestering drugs (e.g., adjudin) that exert their effects on germ cells in the adluminal compartment. The effects of these drugs include disruption of germ cell cycle progression and development, apoptosis, cell adhesion, metabolism and others. Recent studies have demonstrated that there is a functional axis that operates locally in the seminiferous epithelium to co-ordinate different cellular events across the Sertoli cell epithelium, such as spermiation and BTB restructuring during the seminiferous epithelial cycle of spermatogenesis. Components of this functional axis, such as the apical ectoplasmic specialization (apical ES, a testis-specific atypical anchoring junction type) and the BTB, in particular their constituent protein complexes, such as alpha6beta1-integrin and occludin at the apical ES and the BTB, respectively, can be the target of male contraception. In this chapter, we highlight recent advances regarding the likely mechanism of action of adjudin in this functional axis with emphasis on the use of molecular modeling technique to facilitate the design of better compounds in male contraceptive development.