TY - JOUR
T1 - Motor Deficit in a Drosophila Model of Mucolipidosis Type IV due to Defective Clearance of Apoptotic Cells
AU - Venkatachalam, Kartik
AU - Long, A. Ashleigh
AU - Elsaesser, Rebecca
AU - Nikolaeva, Daria
AU - Broadie, Kendal
AU - Montell, Craig
PY - 2008/11/28
Y1 - 2008/11/28
N2 - Disruption of the Transient Receptor Potential (TRP) mucolipin 1 (TRPML1) channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. Here, we report a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects, and neurodegeneration. The basis for the buildup of macromolecules was defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulated in trpml mutant brains, suggesting diminished cell clearance. The accumulation of late-apoptotic cells and motor deficits were suppressed by expression of trpml+ in neurons, glia, or hematopoietic cells. We conclude that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV.
AB - Disruption of the Transient Receptor Potential (TRP) mucolipin 1 (TRPML1) channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. Here, we report a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects, and neurodegeneration. The basis for the buildup of macromolecules was defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulated in trpml mutant brains, suggesting diminished cell clearance. The accumulation of late-apoptotic cells and motor deficits were suppressed by expression of trpml+ in neurons, glia, or hematopoietic cells. We conclude that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV.
KW - CELLBIO
KW - HUMDISEASE
KW - MOLNEURO
UR - http://www.scopus.com/inward/record.url?scp=56349119573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=56349119573&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2008.09.041
DO - 10.1016/j.cell.2008.09.041
M3 - Article
C2 - 19041749
AN - SCOPUS:56349119573
SN - 0092-8674
VL - 135
SP - 838
EP - 851
JO - Cell
JF - Cell
IS - 5
ER -