Brain development is a complex process involving maturation and functional changes in several distinct cell types. One of the key events in brain development is maturation of oligodendrocytes and myelination. It is well known that proliferation of oligodendrocyte precursors, oligodendrocyte maturation and myelination require large amount of iron, but the mechanisms of iron delivery to and utilization by oligodendrocytes are not well understood. Ferritin-dependent iron uptake has been shown to be critical in oligodendrocytes, but post-uptake fate of iron is unclear. We believe that studies of rare diseases linked to hypomyelination and iron handling may shed light on critical processes of brain development. Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in MCOLN1, which encodes the lysosomal ion channel mucolipin-1 (TRPML1). Delayed motor and cognitive development in MLIV patients becomes noticeable in infanthood, and neurologic development arrests at about 15 months and remains stable in the second and third decades of life. In most patients neurologic symptoms include spasticity, hypotonia, an inability to walk independently, ptosis, myopathic faces, drooling, difficulties in chewing and swallowing, and severely impaired fine-motor function. At present, there is no specific treatment for this disease due to poor understanding of its pathogenesis. Mucolipin-1 is known to mediate ion fluxes in the late steps of the endocytic pathway, but the impact of this role in the lysosomes of neurons is unknown. We show that mucolipin-1 loss is associated with changes in cellular iron handling, and provide evidence of hypomyelination and significantly reduced ferric brain iron in the MLIV mouse. We propose that mucolipin-1 loss restricts brain iron uptake and deprives the brain of iron necessary for cell differentiation and myelination. We will identify how loss of mucolipin-1 affects development of oligodendrocytes and subsequently myelination (Aim 1). Next, we will identify the role of mucolipin-1 in cellular iron transport in the brain (Aim 2). Towards the goals outlined in this project, we combine the efforts three labs (Slaugenhaupt, Kiselyov and Connor). Each of the laboratories brings a unique expertise to this project: MLIV neuropathology and mouse model (Slaugenhaupt), MLIV molecular biology and cell-based model systems (Kiselyov), iron regulation of brain myelination (Connor). Iron is vital to brain development, yet mechanisms of its regulation are poorly understood and our data suggests that mucolipin-1 may be an important player. Our findings will provide new information regarding molecular determinants of brain development and maintenance, and will provide insights into potential therapies for this devastating disease.
Iron uptake by brain cells is a key process in brain development, and neurologic impairment due to iron deficiency is common. Mucolipidosis type IV (MLIV) is a lysosomal storage disease resulting in severe delays in motor and cognitive development. Preliminary findings indicate that mucolipin-1 regulates cellular iron traffic, and that the MLIV mouse model shows severe hypomyelination and reduced brain iron levels. This project aims to identify role of mucolipin-1 in brain development by providing a complete account of cell types whose development depends of iron transport by mucolipin-1.
| Ba, Qinle; Raghavan, Guruprasad; Kiselyov, Kirill et al. (2018) Whole-Cell Scale Dynamic Organization of Lysosomes Revealed by Spatial Statistical Analysis. Cell Rep 23:3591-3606 |
| Ravi, Sreeram; Peña, Karina A; Chu, Charleen T et al. (2016) Biphasic regulation of lysosomal exocytosis by oxidative stress. Cell Calcium 60:356-362 |
