Cerebellar alterations and gait defects as therapeutic outcome measures for enzyme replacement therapy in α-mannosidosis

Markus Damme, Stijn Stroobants, Steven U. Walkley, Renate Lüllmann-Rauch, Rudi D'Hooge, Jens Fogh, Paul Saftig, Torben Lübke, Judith Blanz

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)83-94
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2011

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Keywords

  • Cerebellar atrophy
  • Enzyme replacement therapy
  • Gait defects
  • Knockout mouse model
  • Lysosomal storage disease
  • α-Mannosidase
  • α-Mannosidosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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