Current concepts in the neuropathogenesis of mucolipidosis type IV

Abstract

Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease. This review explores our current understanding of the mucolipin-1 protein in relation to neuropathogenesis in MLIV and describes recent findings implicating mucolipin-1's important role in mechanistic target of rapamycin and TFEB (transcription factor EB) signaling feedback loops as well as in the function of the greater endosomal/lysosomal system. In addition to addressing the vital role of mucolipin-1 in the brain, we also report new data on the question of whether haploinsufficiency as would be anticipated in MCOLN1 heterozygotes is associated with any evidence of neuron dysfunction or disease. Greater insights into the role of mucolipin-1 in the nervous system can be expected to shed light not only on MLIV disease but also on numerous processes governing normal brain function. This article is part of the Special Issue "Lysosomal Storage Disorders".

Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells

“…Similarly to TFEB-induced secretion, we find that the secretory pathway elicited by cyclodextrin depends on the endo/lysosomal calcium channel MCOLN1, which is responsible for the LSD mucolipidosis type 4 when mutated (Boudewyn and Walkley, 2018). Previous studies showed that MCOLN1 is involved in the secretion of endo-lysosomal content, since secretion is impaired in MCOLN1 mutant cells (LaPlante et al, 2006), and stimulated by activating MCOLN1 mutations (Dong et al, 2009).…”

“…Similarly, storage in cells from NPC and other LSDs can be reverted by δ-Tocopherol treatment (Xu et al, 2012) or activation of BK channels (Zhong et al, 2016), which also promote endo/lysosome-mediated secretion. Interestingly, the secretion of endo/lysosome storage materials seems to depend on the activation of the lysosomal cation channel mucolipin-1 (MCOLN1), which is itself responsible for the LSD mucolipidosis type 4 when mutated (Boudewyn and Walkley, 2018). Endosome-or lysosomes-mediated secretion is impaired in MCOLN1 mutant cells (LaPlante et al, 2006), while activating mutations in the channel increase the rate of this exocytic pathway (Dong et al, 2009).…”

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

“…Mutations in MCOLN1 disrupt many cellular functions and cause neurodevelopmental disorders by unknown mechanisms. Mucolipin1 is involved in the regulation of fusion/fission of vesicles along the endocytic pathway and in some aspects of the lysosomal Ca 2+ homeostasis [144,145]. Biochemical studies indicate that ML IV-patients suffer from a deficient sialidase activity hydrolyzing gangliosides GM3 and GDla, and an increased urinary excretion of glycolipids and phospholipids [146,147].…”

Lysosomal storage disorders: pathology within the lysosome and beyond

“…Many of the LSDs are associated with significant central nervous system (CNS) pathology, whereas others primarily affect peripheral organs. This Special Issue highlights some of the LSDs that impact the CNS (Bosch and Kielian ; Boudewyn and Walkley ; Burkovetskaya et al . ; Cho et al .…”

“…This Special Issue concludes with a comprehensive synopsis on the neuropathogenesis of mucolipidosis type IV (MLIV) by Boudewyn and Walkley (Boudewyn and Walkley ). MLIV is caused by a mutation in the transient receptor potential channel mucolipin‐1, which is primarily localized to the membrane of late endosomes and lysosomes.…”