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Neurological glycogen storage diseases and emerging therapeutics.
Neurotherapeutics
September 2024
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research (CASBR), University of Florida, Gainesville, FL, USA. Electronic address:
Article Synopsis
- * Patients with n-GSDs show varying neurological symptoms and require different treatment strategies compared to traditional GSDs, as recent studies have uncovered the genetic and biochemical mechanisms behind these conditions.
- * New therapeutic approaches such as enzyme replacement therapy, substrate reduction therapy, and gene therapy have shown promising results in clinical trials, paving the way for improved treatment and better outcomes for n-GSD patients.
Polyglucosan bodies are accumulations of insoluble glucose polymers and proteins that form intracytoplasmic inclusions in the brain, large numbers of which can be indicative of neurodegenerative diseases such as Lafora disease. Montserrat orioles () are an icterid passerine endemic to Montserrat with conservation populations maintained in captivity abroad. We demonstrate that polyglucosan bodies are unusually abundant in the cerebellar molecular and Purkinje cell layers and cerebellar peduncles of captive-bred and wild-caught Montserrat orioles.
View Article and Find Full Text PDFClinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-Cage Behavior.
J Comp Neurol
July 2024
Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments.
View Article and Find Full Text PDFProteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.
Neuropathol Appl Neurobiol
June 2024
Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Aims: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency.
Methods: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.
Amylopectinosis of the fatal epilepsy Lafora disease resists autophagic glycogen catabolism.
EMBO Mol Med
May 2024
Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
In this Correspondence, B. Minassian and colleagues report that GHF201, an autophagy activator shown to diminish abnormal glycogen aggregates in a mouse model of Adult Polyglucosan Body Disease, fails to reduce such accumulations in a mouse model of Lafora disease. [Image: see text]
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