Laforin, the most common protein mutated in Lafora disease, regulates autophagy

Abstract

Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterized by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. However, it is unclear at the moment whether Lafora bodies are the cause of the disease, or whether they are secondary consequences of a primary metabolic alteration. Here we describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy. This phenomenon is confirmed in cell lines from human patients, mouse embryonic fibroblasts from laforin knockout mice and in tissues from such mice. Conversely, laforin expression stimulates autophagy. Laforin regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway. The changes in autophagy mediated by laforin regulate the accumulation of diverse autophagy substrates and would be predicted to impact on the Lafora body accumulation and the cell stress seen in this disease that may eventually contribute to cell death.

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

“…Furthermore, protein aggregates could be reduced by the overexpression of functional laforin, thus providing evidence for a positive regulation of autophagy by laforin. 59 Consistent with these findings, impaired autophagy was observed in brain tissue of malin knockout mice, and experiments in embryonic fibroblasts of these mice revealed a block in autophagosome formation similar to that found in laforin-deficient cells. 60 In contrast, another recent study revealed no changes in LC3-II or other autophagy proteins in brain lysates of another laforin-deficient mouse model, arguing that autophagosome formation and function in the brain of these mice are not critically abnormal.…”

“…[56][57][58] Linking LD to autophagy, a recent study provided evidence for a role of laforin in the regulation of autophagy, potentially through the mTOR pathway. 59 In laforin-deficient fibroblasts obtained from patients and in mouse embryonic fibroblasts and liver tissue derived from laforin knockout mice, the levels of the autophagosome marker LC3-II were significantly reduced, indicating compromised autophagosome formation. 59 Accumulating proteins in these models were found to include the autophagy substrate p62.…”

“…59 In laforin-deficient fibroblasts obtained from patients and in mouse embryonic fibroblasts and liver tissue derived from laforin knockout mice, the levels of the autophagosome marker LC3-II were significantly reduced, indicating compromised autophagosome formation. 59 Accumulating proteins in these models were found to include the autophagy substrate p62. Furthermore, protein aggregates could be reduced by the overexpression of functional laforin, thus providing evidence for a positive regulation of autophagy by laforin.…”

Autophagy: for better or for worse

“…Therefore, autophagy can prevent the emergence of neurodegenerative diseases. Indeed, autophagy protects against aggregation-prone mutant proteins in spinocerebellar ataxia, mutated forms of α-synuclein in Parkinson's disease, mutant Huntingtin in Huntington's disease, tau mutants that cause frontotemporal dementia, pathogenic intraneuronal amyloid beta in Alzheimer disease brain and polyglucosan inclusion bodies in Lafora disease [162,196,[198][199][200][201][202]. Interestingly, most of these neurodegenerative diseases are associated with decreased Beclin-1 levels, which might account for the impaired autophagic clearance.…”

Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers?

“…Biochemical studies have shown that the LD-linked PTG variant indeed displayed decreased ability to promote the glycogen synthesis. 23 Beyond glycogen synthesis, the laforin-malin complex is thought to be involved in other cellular pathways such as endoplasmic reticulum stress, 28 clearance of misfolded proteins via the ubiquitin-proteasome pathway or autophagy 11,[29][30][31] and the heat shock response 12 (see Table 1). It would be therefore important to check possible contributions of sequence variations in critical regulators of these pathways that interact with laforin and/or malin, and test their possible role as modifiers in LD.…”