Endocrinology, Diabetes and Hypertension

Janice LaPlante, Ph.D.

Dr. LaPlante is investigating the role of the cation channel mucolipin-1in late endosomal/lysosomal trafficking.   Mucolipidosis Type IV (ML4) is an autosomal recessive disorder characterized by severe cognitive and developmental delays, corneal clouding leading to loss of vision and gastric dysfunction. Although initially thought to be limited to a small number of families of Ashkenazi Jewish descent, the recent cloning of the MLIV gene, MCOLN1, has indicated that the disorder may be more prevalent in the human population than was previously believed. Similar to the lysosomal storage diseases whose patients also display severe neurological defects and the progressive onset of blindness, MLIV patients have large autofluorescent cellular inclusions resembling lysosomes in many cells and tissues, which appear as “dense bodies” under electron microscopy. However, the defect in MLIV does not appear to lie in the abnormal catabolism of proteins and lipids, but in a deficiency in membrane transport in the late endosomal/lysosomal pathway. Mucolipin-1 (MLN1), the protein encoded by the MCOLN1 gene, shares significant sequence homology with TRP and other cation channels. It is a nonspecific cation channel that is transiently modulated by Ca²⁺ on both sides of the membranes where it is expressed. Naturally occurring mutant MLN1 channels are weakly activated by increases in intracellular Ca²⁺ (Ca_i) and show other functional abnormalities. With their high permeability and sensitivity to Ca²⁺ the MLN1 channels may play a major role in transmembrane Ca²⁺ transport across lysosomal and related organelle membranes. Our data supports the premise that at the molecular level, MLN1 is a channel playing a role in Ca²⁺ release from late endosomal/lysosomal (LEL) lumenal compartments, a step required for the fusion between these organelles. The abnormally enlarged lysosomal structures that are typical path morphological features in MLIV patients are likely to be intermediates in the stalled Ca2+-dependent fusion process. At the cellular level, our data suggests that MLN1 plays a permissive role that acts at a number of levels during LEL trafficking.

Current Projects:

1. To determine the normal function of MLN1 in LEL trafficking in fibroblasts and CNS models.
2. To determine the pathophysiological mechanism by which a loss of function of MLN1 leads to neurological dysfunction and the MLIV phenotype.

1. LaPlante JM,Falardeau J, Sun M, Kanazirska M, Brown EM, Slaugenhaupt SA, Vassilev PM. Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway. FEBS Lett.2002 Dec 4;532(1-2):183-7.
2. LaPlante JM,Ye CP, Quinn SJ, Goldin E, Brown EM, Slaugenhaupt SA, Vassilev PM. Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV. Biochem Biophys Res Commun. 2004 Oct 1;322(4):1384-91.