Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration.

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

One of the most intriguing problems in developmental biology is how an organism can replace missing organs or portions of its body after injury. This capacity, known as regeneration, is conserved across different phyla. The imaginal discs of Drosophila melanogaster provide a particularly well-characterized model for analyzing regeneration. We have developed a unique method to study organ regeneration under physiological conditions using the imaginal discs of Drosophila. Using this method, we revisited different aspects of organ regeneration. The results presented in this report suggest that during the initial stages of regeneration, different processes occur, including wound healing, a temporary loss of markers of cell-fate commitment, and pattern reorganization. We present evidence indicating that all of these processes occur even when cell division has been arrested. Our data also suggested that Wingless is not required during the early stages of disc regeneration.epimorphic | morphallatic R egeneration allows for the replacement of missing organs or body parts when they are damaged. In 1901, Morgan (1) proposed two different regenerative models: regeneration that allows for the reconstruction of the lost structure as a result of regenerative growth and regeneration that remodels the remaining tissues without proliferation. The first model is an addon regeneration, known as epimorphic regeneration, which has been extensively studied in different organisms (2). In these animals, after the amputation of a portion of the limb, a group of differentiated cells near the injured region dedifferentiate and form the blastema (3). These cells then proliferate to reconstruct the amputated structure. In contrast, in the second model of regeneration, which is known as morphallactic regeneration, tissue remodeling and the redifferentiation of cells in the absence of proliferation occurs (4).The imaginal discs of Drosophila have been used as a classical model for the study of the genetic and molecular basis of organ regeneration (review by ref. 5). These structures give rise to the adult organs of Drosophila. The imaginal wing disc is the precursor of the wing and notum in the adult. Cells that constitute these discs begin to divide during the first larval stage and continue proliferating until the end of larval development, and it is during this time that the characteristics of the adult wings are defined (6).The standard approach used to study regeneration in Drosophila has been to grow the regenerating structures in an in vivo culture. The disc is extracted from the larva and, after removing a fragment of it, transplanted into the abdomen of an adult host where the cells proliferate but do not differentiate (7,8). The results obtained from these experiments revealed a zone of high cell proliferation on the edges of the wound, similar to the blastema that originates during limb regeneration in amphibians (9, 10). These studies suggest that the regeneration of lost structures in Drosophila is the result of regenerative grow...