TY - JOUR
T1 - Neuropathology of the Mcoln1-/- knockout mouse model of mucolipidosis type IV
AU - Micsenyi, Matthew C.
AU - Dobrenis, Kostantin
AU - Stephney, Gloria
AU - Pickel, James
AU - Vanier, Marie T.
AU - Slaugenhaupt, Susan A.
AU - Walkley, Steven U.
PY - 2009/2
Y1 - 2009/2
N2 - The recently developed Mcoln1 knockout mouse provides a novel model for analyzing mucolipin 1 function and mucolipidosis type IV disease. Here we characterize the neuropathology of Mcoln1 mouse at the end stage. Evidence of ganglioside accumulation, including increases in GM2, GM3, and GD3 and redistribution of GM1, was found throughout the central nervous system (CNS) independent of significant cholesterol accumulation. Unexpectedly, colocalization studies using immunofluorescence confocal microscopy revealed that GM1 and GM2 were present in separate vesicles within individual neurons. While GM2 was significantly colocalized with LAMP2, consistent with late-endosomal/lysosomal processing, some GM2-immunoreactivity occurred in LAMP2-negative sites, suggesting involvement of other vesicular systems. P62/Sequestosome 1 (P62/SQSTM1) inclusions were also identified in the CNS of the Mcoln1 mouse, suggesting deficiencies in protein degradation. Glial cell activation was increased in brain, and there was evidence of reduced myelination in cerebral and cerebellar white matter tracts. Autofluorescent material accumulated throughout the brains of the knockout mice. Finally, axonal spheroids were prevalent in white matter tracts and Purkinje cell axons. This neuropathological characterization of the Mcoln1 mouse provides an important step in understanding how mucolipin 1 loss of function affects the CNS and contributes to mucolipidosis type IV disease.
AB - The recently developed Mcoln1 knockout mouse provides a novel model for analyzing mucolipin 1 function and mucolipidosis type IV disease. Here we characterize the neuropathology of Mcoln1 mouse at the end stage. Evidence of ganglioside accumulation, including increases in GM2, GM3, and GD3 and redistribution of GM1, was found throughout the central nervous system (CNS) independent of significant cholesterol accumulation. Unexpectedly, colocalization studies using immunofluorescence confocal microscopy revealed that GM1 and GM2 were present in separate vesicles within individual neurons. While GM2 was significantly colocalized with LAMP2, consistent with late-endosomal/lysosomal processing, some GM2-immunoreactivity occurred in LAMP2-negative sites, suggesting involvement of other vesicular systems. P62/Sequestosome 1 (P62/SQSTM1) inclusions were also identified in the CNS of the Mcoln1 mouse, suggesting deficiencies in protein degradation. Glial cell activation was increased in brain, and there was evidence of reduced myelination in cerebral and cerebellar white matter tracts. Autofluorescent material accumulated throughout the brains of the knockout mice. Finally, axonal spheroids were prevalent in white matter tracts and Purkinje cell axons. This neuropathological characterization of the Mcoln1 mouse provides an important step in understanding how mucolipin 1 loss of function affects the CNS and contributes to mucolipidosis type IV disease.
KW - Axonal spheroids
KW - Bis(monoacylglycero) phosphate
KW - Gangliosides
KW - Lysosomal disease
KW - Mucolipin 1
KW - P62/Sequestosome 1
UR - http://www.scopus.com/inward/record.url?scp=64049105423&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64049105423&partnerID=8YFLogxK
U2 - 10.1097/NEN.0b013e3181942cf0
DO - 10.1097/NEN.0b013e3181942cf0
M3 - Article
C2 - 19151629
AN - SCOPUS:64049105423
SN - 0022-3069
VL - 68
SP - 125
EP - 135
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 2
ER -