Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

Kitakaze, Keisuke; Mizutani, Yasumichi; Sugiyama, Eiji; Tasaki, Chikako; Tsuji, Daisuke; Maita, N.; Hirokawa, Takatsugu; Asanuma, Daisuke; Kamiya, Mako; Sato, Kohei; Setou, Mitsutoshi; Urano, Yasuteru; Togawa, Tadayasu; Otaka, Akira; Sakuraba, Hitoshi; Itoh, Kohji

doi:10.1172/jci85300

Cited by 28 publications

(24 citation statements)

References 62 publications

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“…The key strength of IMS compared to common imaging techniques is the ability to provide spatial localization of chemical species together with quantitative estimates as particularly illustrated previously for ganglioside species in the brain [24–26]. Similarly, the distribution of various gangliosides in rodent brain has been reported in other recent studies [50–52]. Here, a characteristic increase of cortical GM2 and GM3 levels was reported in a Hunter’s disease (HD) mouse model [53].…”

Section: Resultsmentioning

confidence: 69%

MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure

Karlsson

Michno

Ransome

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The environmental toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative diseases. We have previously shown that neonatal exposure to BMAA results in dose-dependent cognitive impairments, proteomic alterations and progressive neurodegeneration in the hippocampus of adult rats. A high BMAA dose (460 mg/kg) also induced intracellular fibril formation, increased protein ubiquitination and enrichment of proteins important for lipid transport and metabolism. The aim of this study was therefore to elucidate the role of neuronal lipids in BMAA-induced neurodegeneration. By using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we characterized the spatial lipid profile in the hippocampus of six month-old rats that were treated neonatally (postnatal days 9–10) with 460 mg/kg BMAA. Multivariate statistical analysis revealed long-term changes in distinct ganglioside species (GM, GD, GT) in the dentate gyrus. These changes could be a consequence of direct effects on ganglioside biosynthesis through the b-series (GM3-GD3-GD2-GD1b-GT1b) and may be linked to astrogliosis. Complementary immunohistochemistry experiments towards GFAP and S100β further verified the role of increased astrocyte activity in BMAA-induced brain damage. This highlights the potential of imaging MS for probing chemical changes associated with neuropathological mechanisms in situ.

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Section: Resultsmentioning

confidence: 69%

MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure

Karlsson

Michno

Ransome

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…Thus, in proof-of-principle studies of chronic ERT in mouse models, success has been modest in terms of extending survival and improving phenotypes of LSDs. For example, in a recent study, 17 GM2 gangliosidosis mice were treated with chronic ICV administration of a modified β-hexosaminidase A, and this increased median survival by 22% and slowed, but did not prevent, locomotor decline.…”

Section: Discussionmentioning

confidence: 99%

Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease

Wiseman

Yan-fa

Nemtsova

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.

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“…by HsHEXa [43][44][45]. Loop 2 of HsHEXb contains residues D452 and L453 at the equivalent positions.…”

Section: Variable Structural Elements Shape the Active Pocketmentioning

confidence: 99%

“…9). The active pocket of HsHEXa differs from that of HsHEXb at only two residues-N423 and R424, located in loop 2 [44]; the asparagine residue binds the inhibitor NGT (see also Fig. 5) [25].…”

Section: Variable Structural Elements Shape the Active Pocketmentioning

confidence: 99%

Crystal structure of native β‐N‐acetylhexosaminidase isolated from Aspergillus oryzae sheds light onto its substrate specificity, high stability, and regulation by propeptide

et al. 2017

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Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

Cited by 28 publications

References 62 publications

MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure

MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure

Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease

Crystal structure of native β‐N‐acetylhexosaminidase isolated from Aspergillus oryzae sheds light onto its substrate specificity, high stability, and regulation by propeptide

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