No abstract

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

People tend to close their eyes when trying to retrieve an event or a visual image from memory. However the brain mechanisms behind this phenomenon remain poorly understood. Recently, we showed that during visual mental imagery, auditory areas show a much more robust deactivation than during visual perception. Here we ask whether this is a special case of a more general phenomenon involving retrieval of intrinsic, internally stored information, which would result in crossmodal deactivations in other sensory cortices which are irrelevant to the task at hand. To test this hypothesis, a group of 9 sighted individuals were scanned while performing a memory retrieval task for highly abstract words (i.e., with low imaginability scores). We also scanned a group of 10 congenitally blind, which by definition do not have any visual imagery per se. In sighted subjects, both auditory and visual areas were robustly deactivated during memory retrieval, whereas in the blind the auditory cortex was deactivated while visual areas, shown previously to be relevant for this task, presented a positive BOLD signal. These results suggest that deactivation may be most prominent in task-irrelevant sensory cortices whenever there is a need for retrieval or manipulation of internally stored representations. Thus, there is a task-dependent balance of activation and deactivation that might allow maximization of resources and filtering out of non relevant information to enable allocation of attention to the required task. Furthermore, these results suggest that the balance between positive and negative BOLD might be crucial to our understanding of a large variety of intrinsic and extrinsic tasks including high-level cognitive functions, sensory processing and multisensory integration.