Molecular and cellular basis of lysosomal transmembrane protein dysfunction

Abstract

Lysosomal membrane proteins act at several crucial steps of the lysosome life cycle, including lumen acidification, metabolite export, molecular motor recruitment and fusion with other organelles. This review summarizes the molecular mechanisms of lysosomal storage diseases caused by defective transport of small molecules or ions across the lysosomal membrane, as well as Danon disease. In cystinosis and free sialic acid storage diseases, transporters for cystine and acidic monosaccharides, respectively, are blocked or retarded. A putative cobalamin transporter and a hybrid transporter/transferase of acetyl groups are defective in cobalamin F type disease and mucopolysaccharidosis type IIIC, respectively. In neurodegenerative forms of osteopetrosis, mutations of a proton/chloride exchanger impair the charge balance required for sustained proton pumping by the V-type ATPase, thus resulting in bone-resorption lacuna neutralization. However, the mechanism leading to lysosomal storage and neurodegeneration remains unclear. Mucolipidosis type IV is caused by mutations of a lysosomal cation channel named TRPML1; its gating properties are still poorly understood and the ion species linking this channel to lipid storage and membrane traffic defects is debated. Finally, the autophagy defect of Danon disease apparently arises from a role of LAMP2 in lysosome/autophagosome fusion, possibly secondary to a role in dynein-based centripetal motility.

Loss of Lysosomal Ion Channel Transient Receptor Potential Channel Mucolipin-1 (TRPML1) Leads to Cathepsin B-dependent Apoptosis

“…Its mechanisms in lysosomal storage disorders, however, are not well understood. Some of the current models, including suppressed flow of key substrates or accumulation of effete organelles due to autophagy block, have been discussed (25,59,60). Here we show that in addition to the "supply side" issues in lysosomal storage diseases, an active and early CatB release mechanism specifically caused by TRPML1 loss takes place soon after TRPML1 KD.…”

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

“…Consistent with this postulation, overexpression of ATP13A2 resulted in a reduced intracellular Mn 2ϩ concentration. Moreover, neurodegeneration with brain iron accumulation and other neuronal system diseases are caused by defects in lysosomal membrane proteins (37,38). Even though no specific substrate of ATP13A2 has been identified, brain MRIs indicate that patients with ATP13A2 mutations show generalized atrophy of the putaminal and caudate with bilateral iron accumulation (2,9).…”

Autophagic flux induced by graphene oxide has a neuroprotective effect against human prion protein fragments

“…6,7 Autophagosomes fuse with lysosomes to form autolysosomes, mediated by a receptor in the lysosomal membrane -the lysosome-associated membrane protein 2 (Lamp-2). 10 In the autolysosomes, the luminal cargo is degraded by lysosomal enzymes. 6,7,10 Some studies have shown that activation of autophagic flux plays a crucial role in a variety of conditions, including tumor suppression, immune A previous study from our laboratory showed melatonin protects neuronal cells against prion protein (PrP) (106-126)-mediated mitochondrial neurotoxicity via upregulation of autophagy.…”

“…10 In the autolysosomes, the luminal cargo is degraded by lysosomal enzymes. 6,7,10 Some studies have shown that activation of autophagic flux plays a crucial role in a variety of conditions, including tumor suppression, immune A previous study from our laboratory showed melatonin protects neuronal cells against prion protein (PrP) (106-126)-mediated mitochondrial neurotoxicity via upregulation of autophagy. 12 Moreover, GO can simultaneously trigger an antitumor effect and activate an immune response through activation of autophagic flux.…”