Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice.

TY - JOUR

T1 - Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice.

AU - Kollmann, Katrin

AU - Damme, M

AU - Markmann, Sandra

AU - Morelle, W

AU - Schweizer, Michaela

AU - Hermans-Borgmeyer, Irmgard

AU - Röchert, Anna Katharina

AU - Pohl, Sandra

AU - Lübke, T

AU - Michalski, J-C

AU - Käkelä, R

AU - Walkley, S U

AU - Braulke, Thomas

PY - 2012

Y1 - 2012

N2 - Mucolipidosis II is a neurometabolic lysosomal trafficking disorder of infancy caused by loss of mannose 6-phosphate targeting signals on lysosomal proteins, leading to lysosomal dysfunction and accumulation of non-degraded material. However, the identity of storage material and mechanisms of neurodegeneration in mucolipidosis II are unknown. We have generated 'knock-in' mice with a common mucolipidosis II patient mutation that show growth retardation, progressive brain atrophy, skeletal abnormalities, elevated lysosomal enzyme activities in serum, lysosomal storage in fibroblasts and brain and premature death, closely mimicking the mucolipidosis II disease in humans. The examination of affected mouse brains at different ages by immunohistochemistry, ultrastructural analysis, immunoblotting and mass spectrometric analyses of glycans and anionic lipids revealed that the expression and proteolytic processing of distinct lysosomal proteins such as ?-l-fucosidase, ?-hexosaminidase, ?-mannosidase or Niemann-Pick C2 protein are more significantly impacted by the loss of mannose 6-phosphate residues than enzymes reaching lysosomes independently of this targeting mechanism. As a consequence, fucosylated N-glycans, GM2 and GM3 gangliosides, cholesterol and bis(monoacylglycero)phosphate accumulate progressively in the brain of mucolipidosis II mice. Prominent astrogliosis and the accumulation of organelles and storage material in focally swollen axons were observed in the cerebellum and were accompanied by a loss of Purkinje cells. Moreover, an increased neuronal level of the microtubule-associated protein 1 light chain 3 and the formation of p62-positive neuronal aggregates indicate an impairment of constitutive autophagy in the mucolipidosis II brain. Our findings demonstrate the essential role of mannose 6-phosphate for selected lysosomal proteins to maintain the capability for degradation of sequestered components in lysosomes and autophagolysosomes and prevent neurodegeneration. These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease.

AB - Mucolipidosis II is a neurometabolic lysosomal trafficking disorder of infancy caused by loss of mannose 6-phosphate targeting signals on lysosomal proteins, leading to lysosomal dysfunction and accumulation of non-degraded material. However, the identity of storage material and mechanisms of neurodegeneration in mucolipidosis II are unknown. We have generated 'knock-in' mice with a common mucolipidosis II patient mutation that show growth retardation, progressive brain atrophy, skeletal abnormalities, elevated lysosomal enzyme activities in serum, lysosomal storage in fibroblasts and brain and premature death, closely mimicking the mucolipidosis II disease in humans. The examination of affected mouse brains at different ages by immunohistochemistry, ultrastructural analysis, immunoblotting and mass spectrometric analyses of glycans and anionic lipids revealed that the expression and proteolytic processing of distinct lysosomal proteins such as ?-l-fucosidase, ?-hexosaminidase, ?-mannosidase or Niemann-Pick C2 protein are more significantly impacted by the loss of mannose 6-phosphate residues than enzymes reaching lysosomes independently of this targeting mechanism. As a consequence, fucosylated N-glycans, GM2 and GM3 gangliosides, cholesterol and bis(monoacylglycero)phosphate accumulate progressively in the brain of mucolipidosis II mice. Prominent astrogliosis and the accumulation of organelles and storage material in focally swollen axons were observed in the cerebellum and were accompanied by a loss of Purkinje cells. Moreover, an increased neuronal level of the microtubule-associated protein 1 light chain 3 and the formation of p62-positive neuronal aggregates indicate an impairment of constitutive autophagy in the mucolipidosis II brain. Our findings demonstrate the essential role of mannose 6-phosphate for selected lysosomal proteins to maintain the capability for degradation of sequestered components in lysosomes and autophagolysosomes and prevent neurodegeneration. These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease.

KW - Animals

KW - Disease Models, Animal

KW - Mice

KW - Atrophy

KW - Mice, Transgenic

KW - Autophagy

KW - Brain/enzymology/pathology

KW - Lysosomes/enzymology/genetics/pathology

KW - Mucolipidoses/enzymology/genetics/pathology

KW - Nerve Degeneration/enzymology/genetics/pathology

KW - Vesicular Transport Proteins/metabolism

KW - alpha-L-Fucosidase/metabolism

KW - alpha-Mannosidase/metabolism

KW - beta-N-Acetylhexosaminidases/metabolism

KW - Animals

KW - Disease Models, Animal

KW - Mice

KW - Atrophy

KW - Mice, Transgenic

KW - Autophagy

KW - Brain/enzymology/pathology

KW - Lysosomes/enzymology/genetics/pathology

KW - Mucolipidoses/enzymology/genetics/pathology

KW - Nerve Degeneration/enzymology/genetics/pathology

KW - Vesicular Transport Proteins/metabolism

KW - alpha-L-Fucosidase/metabolism

KW - alpha-Mannosidase/metabolism

KW - beta-N-Acetylhexosaminidases/metabolism

M3 - SCORING: Journal article

VL - 135

SP - 2661

EP - 2675

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - Pt 9

M1 - Pt 9

ER -