Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Abstract

Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria–pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation.

Different Doublecortin (DCX) Patient Alleles Show Distinct Phenotypes in Cultured Neurons

“…Cortical malformations are recovered in the human populations at a surprisingly high rate and can be familial or arise spontaneously de novo (1)(2)(3)28). One manifestation of cortical malformation is subcortical band heterotopia (SBH) and lissencephaly (LIS; smooth brain).…”

“…We thus used dendrite enhancement by Dcx expression as an assay for wild type Dcx function, using previously described MT binding-competent and MT bindingdeficient mutants (25)(26)(27). All of these alleles were originally identified in patients with lissencephaly (2,28,29). We found that Dcx alleles that retain MT binding but lack the C-terminal regions (required for spn and AP adaptor binding) are defective for dendrite growth promotion (i.e.…”

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

“…7 Functional studies suggest that abnormal neuronal migration would result from defective interactions in the tubulin heterodimer assembly and altered three-dimensional conformation of the tubulins, with compromised interaction with microtubule-associated proteins or microtubule motors. 11 This study brings to eight the number of individuals with TUBB2B mutations reported so far. We identified three new TUBB2B mutations in as many unrelated patients with rather symmetrical malformations of cortical development, including polymicrogyria in two patients, one having a cobblestone-like cortex, and bilateral regional pachygyria in one.…”

Calcium Signaling in Neuronal Motility: Pharmacological Tools for Investigating Specific Pathways

“…It has been shown that Reelin interacts, via membrane receptors, with motor and cytoskeletal proteins [94,95], likely targets of calcium dependent pathways. Actually, it has been shown that the product of the LIS1 gene, whose mutation leads to Type I lissencephaly, regulates in a calcium influx-dependent way some RhoGTPases involved in cytoskeletal dynamics [96].…”

“…It can be envisioned that future focus will be, more than on calcium signalling per se, on the field of calcium-dependent proteins involved in cytoskeletal organization and in organelle trafficking, as pointed by the Reelinlissencephaly case [94][95][96]. However, it cannot be excluded that the TRP channel superfamily, just a newcomer in this context, may provide some surprise -and some unexpected answers.…”