Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature–inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of lncRNAs have newly appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. lncRNAs are increasingly reported to be involved in neurodevelopmental processes suggested to underlie human brain evolution, including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review.

Hereditary spastic paraplegias (HSPs) are characterized by progressive weakness and spasticity of the legs because of the degeneration of cortical motoneuron axons. SPG15 is a recessively inherited HSP variant caused by mutations in the ZFYVE26 gene and is additionally characterized by cerebellar ataxia, mental decline, and progressive thinning of the corpus callosum. ZFYVE26 encodes the FYVE domain-containing protein ZFYVE26/SPASTIZIN, which has been suggested to be associated with the newly discovered adaptor protein 5 (AP5) complex. We show that Zfyve26 is broadly expressed in neurons, associates with intracellular vesicles immunopositive for the early endosomal marker EEA1, and co-fractionates with a component of the AP5 complex. As the function of ZFYVE26 in neurons was largely unknown, we disrupted Zfyve26 in mice. Zfyve26 knockout mice do not show developmental defects but develop late-onset spastic paraplegia with cerebellar ataxia confirming that SPG15 is caused by ZFYVE26 deficiency. The morphological analysis reveals axon degeneration and progressive loss of both cortical motoneurons and Purkinje cells in the cerebellum. Importantly, neuron loss is preceded by accumulation of large intraneuronal deposits of membrane-surrounded material, which co-stains with the lysosomal marker Lamp1. A density gradient analysis of brain lysates shows an increase of Lamp1-positive membrane compartments with higher densities in Zfyve26 knockout mice. Increased levels of lysosomal enzymes in brains of aged knockout mice further support an alteration of the lysosomal compartment upon disruption of Zfyve26. We propose that SPG15 is caused by an endolysosomal membrane trafficking defect, which results in endolysosomal dysfunction. This appears to be particularly relevant in neurons with highly specialized neurites such as cortical motoneurons and Purkinje cells. Hereditary spastic paraplegias (HSPs) are inherited disorders characterized by progressive weakness and spasticity of the legs. In HSP patients, nerve fibers connecting cortical motoneurons with spinal cord neurons are progressively lost. HSP subtype 15 (SPG15) is caused by mutations in ZFYVE26, and is characterized by additional cerebellar symptoms. We show that the Zfyve26 protein is broadly expressed in the brain. At the subcellular level Zfyve26 localizes to an intracellular compartment in the endocytic pathway from the plasma membrane to lysosomes, which is part of the degradative system of the cell. Closely resembling the human disease, mice deficient for Zfyve26 develop a progressive spastic gait disorder with cerebellar symptoms and degeneration of both neurons of the motor cortex and Purkinje cells in the cerebellum. Importantly, this degeneration is characterized by the intracellular accumulation of abnormal deposits, which stain positive for the lysosomal marker Lamp1. As Zfyve26 has been shown to interact with the newly identified adaptor complex AP5, which is supposed to be involved in cargo trafficking in the endolysosomal compartment, endolysosomal dysfunction may be caused by a targeting defect upon disruption of Zfyve26. As highly specialized neurons like cortical motoneurons and cerebellar Purkinje cells degenerate, these neurons appear to be particularly dependent on proper endolysosomal function.

The integration of interneuron subtypes into specific microcircuits is essential for proper cortical function. Understanding to what extent interneuron diversity is regulated and maintained during development might help to reveal the principles that govern their role as synchronizing elements as well as causes for dysfunction. Particular interneuron subtypes are generated in a temporally regulated manner in the medial ganglionic eminence (MGE), the caudal ganglionic eminence, and the preoptic area (POA) of the basal telencephalon. Long-range tangential migration from their site of origin to cortical targets is orchestrated by a variety of attractive, repulsive, membrane-bound, and secreted signaling molecules, to establish the critical balance of inhibition and excitation. It remains unknown whether interneurons deriving from distinct domains are predetermined to migrate in particular routes and whether this process underlies cell type-specific regulation. We found that POA- and MGE-derived cortical interneurons migrate within spatially segregated corridors. EphrinB3, expressed in POA-derived interneurons traversing the superficial route, acts as a repellent signal for deeply migrating interneurons born in the MGE, which is mediated by EphA4 forward signaling. In contrast, EphA4 induces repulsive ephrinB3 reverse signaling in interneurons generated in the POA, restricting this population to the superficial path. Perturbation of this bidirectional ephrinB3/EphA4 signalingin vitroandin vivoleads to a partial intermingling of cells in these segregated migratory pathways. Thus, we conclude that cell contact-mediated bidirectional ephrinB3/EphA4 signaling mediates the sorting of MGE- and POA-derived interneurons in the deep and superficial migratory stream.