Cerebellar alterations and gait defects as therapeutic outcome measures for enzyme replacement therapy in alpha-mannosidosis
Autor: | Paul Saftig, Judith Blanz, Renate Lüllmann-Rauch, Markus Damme, Jens Fogh, Stijn Stroobants, Torben Lübke, Steven U. Walkley, Rudi D'Hooge |
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Jazyk: | angličtina |
Rok vydání: | 2011 |
Předmět: |
medicine.medical_specialty
Cerebellum Alpha-mannosidosis Lameness Animal CHO Cells Biology Article Pathology and Forensic Medicine Mannosidosis 03 medical and health sciences Cellular and Molecular Neuroscience Mice Mice Neurologic Mutants 0302 clinical medicine Atrophy Cricetulus alpha-Mannosidase Internal medicine Cricetinae medicine Lysosomal storage disease Animals Humans Enzyme Replacement Therapy 030304 developmental biology Mice Knockout 0303 health sciences General Medicine Enzyme replacement therapy medicine.disease Metachromatic leukodystrophy Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Endocrinology Treatment Outcome Neurology Gene Targeting alpha-Mannosidosis Cerebellar atrophy Neurology (clinical) 030217 neurology & neurosurgery |
Zdroj: | Journal of Neuropathology and Experimental Neurology; Vol 70 |
Popis: | 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. |
Databáze: | OpenAIRE |
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