Lafora disease, also called Lafora progressive myoclonic epilepsy, is a fatal autosomal recessive genetic disorder characterized by the presence of inclusion bodies, known as Lafora bodies, within neurons and the cells of the heart, liver, muscle, and skin.
Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable
Progressive myoclonus epilepsy of the Lafora type (Lafora disease, LD, OMIM 274780) is a rare disease characterized by the presence of neurodegeneration, epilepsy and accumulation of poorly branched polyglycosans in different tissues. This disease leads to the death of the patient around 10 years from the onset. At the moment only a limited knowledge about the molecular bases of the disease is known and there is no available treatment.
The classical form of the disease depends on mutations of 2 genes:
age, sex, seasonality, etc
A large body,surrounded by a clear halo, is characteristic of myoclonic epilepsy and is illustrated in the image above. They are called Lafora's bodies, due to accumulation of polyglucosans.
LD is a recessive autosomic disease and so far two genes have been described to be involved in the pathogenesis of the disease: EPM2A and EPM2B.
- EPM2A codes for a protein called laforin which has a carbohydrate binding domain (CBD) at the N-terminus and a dual specificity phosphatase (DSP) domain at the C-terminus.
- EPM2B codes for a protein called malin (with E3-ubiquitin ligase activity), which has a RING finger domain at the N-terminus and six NHL domains at the C-terminus involved in protein-protein interaction.
Recently, our group (Dr. Pascual Sanz Bigorra) has described that laforin and malin form a functional complex, suggesting that both proteins participate in a common physiological process and justifying why patients with mutation in either EPM2A or EPM2B are neurologically and histologically indistinguishable.
Laforin/malin Complex Main function
One of the functions of this complex is to downregulate the levels of R5/PTG, a protein involved in the upregulation of glycogen synthesis.
This function would explain why in the absence of a functional laforin-malin complex, cells would accumulate polyglycosans (a pathological determinant of the disease).
In the complex, laforin acts as a targeting subunit of malin, being able to recognize different substrates that eventually will be ubiquitinated by malin and targeted for degradation.
In addition to the role that laforin and malin may have on the regulation of glycogen synthesis, these proteins have alternative roles in cellular physiology. For this reason, we are studying the involvement laforin and malin in the regulation of different signalling pathways, such as those involving AMPK. These new regulatory functions of laforin and malin will help us to understand the pathophysiology of the disease and to define possible therapeutic targets.
Recently, it has been described that laforin and malin are localized around the endoplasmic reticulum (ER) and that, after conditions of proteasome inhibition, these two proteins form aggregates that include ER chaperones, E2-ubiquin ligases and proteasome subunits. Since this manifestation is similar to other conditions of ER-stress, and since it has been described that maintained ER-stress may lead to apoptosis and neurodegeneration (another pathologic determinant of Lafora disease), we are studying whether the process of ER-stress is altered in samples from Lafora disease patients. To confirm this point we are also using cultured cell lines lacking either laforin or malin and animal models of the disease (EPM2A or EPM2B KO mice).
(A) GS (light blue) extends the growing glycogen chain in a linear manner. GBE1 (green) branches the linear glycogen, giving the molecule its spherical shape. If the balance between extension and branching is disrupted, poorly branched glycogen, or polyglucosans, form instead of normal glycogen. Laforin, malin, and, possibly, other proteins involved in Lafora disease regulate the balance of the two enzymes, preventing polyglucosan formation. (B) Glycogen is normally phosphorylated, and this hinders its degradation. Laforin (yellow) dephosphorylates glycogen. Laforin must then be removed to enable degradation to start, and this is accomplished by malin (red circle). If laforin or malin is not present, glycogen cannot be degraded and, over time, it loses its spherical structure, accumulating as polyglucosans to form Lafora bodies. Abbreviations: GBE1, glycogen branching enzyme; GS, glycogen synthase; P, phosphate.
Typical progression of myoclonic epilepsy of the Lafora type: a case report 2007
PATIENT RISK FACTORS
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)