TY - JOUR
T1 - Cerebellar alterations and gait defects as therapeutic outcome measures for enzyme replacement therapy in α-mannosidosis
AU - Damme, Markus
AU - Stroobants, Stijn
AU - Walkley, Steven U.
AU - Lüllmann-Rauch, Renate
AU - D'Hooge, Rudi
AU - Fogh, Jens
AU - Saftig, Paul
AU - Lübke, Torben
AU - Blanz, Judith
PY - 2011/1
Y1 - 2011/1
N2 - α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions, and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages, and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-Mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term enzyme replacement therapy partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides, and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures.
AB - α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions, and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages, and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-Mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term enzyme replacement therapy partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides, and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures.
KW - Cerebellar atrophy
KW - Enzyme replacement therapy
KW - Gait defects
KW - Knockout mouse model
KW - Lysosomal storage disease
KW - α-Mannosidase
KW - α-Mannosidosis
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UR - http://www.scopus.com/inward/citedby.url?scp=78650676578&partnerID=8YFLogxK
U2 - 10.1097/NEN.0b013e31820428fa
DO - 10.1097/NEN.0b013e31820428fa
M3 - Article
C2 - 21157375
AN - SCOPUS:78650676578
SN - 0022-3069
VL - 70
SP - 83
EP - 94
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 1
ER -