Pathogenesis of lafora disease: Transition of soluble glycogen to insoluble polyglucosan

Mitchell A. Sullivan, Silvia Nitschke, Martin Steup, Berge A. Minassian, Felix Nitschke

Research output: Contribution to journalReview article

17 Citations (Scopus)

Abstract

Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD.

Original languageEnglish (US)
Article number1743
JournalInternational Journal of Molecular Sciences
Volume18
Issue number8
DOIs
StatePublished - Aug 11 2017

Fingerprint

Lafora Disease
glycogens
pathogenesis
Glycogen
impairment
Chain length
Progressive Myoclonic Epilepsy
epilepsy
Neurodegenerative diseases
Genetic Databases
Autophagy
paradoxes
Hand Strength
metabolism
mutations
cultured cells
Metabolism
Neurodegenerative Diseases
genes
mice

Keywords

  • Chain length distribution
  • Glycogen phosphorylation
  • Lafora disease
  • Laforin
  • Malin
  • Polyglucosan body

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Pathogenesis of lafora disease : Transition of soluble glycogen to insoluble polyglucosan. / Sullivan, Mitchell A.; Nitschke, Silvia; Steup, Martin; Minassian, Berge A.; Nitschke, Felix.

In: International Journal of Molecular Sciences, Vol. 18, No. 8, 1743, 11.08.2017.

Research output: Contribution to journalReview article

Sullivan, Mitchell A. ; Nitschke, Silvia ; Steup, Martin ; Minassian, Berge A. ; Nitschke, Felix. / Pathogenesis of lafora disease : Transition of soluble glycogen to insoluble polyglucosan. In: International Journal of Molecular Sciences. 2017 ; Vol. 18, No. 8.
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