These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS.

Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1 ؊/؊ mice, which display a proportional decrease in the sizes of all organs, Akt3 ؊/؊ mice present a selective 20% decrease in brain size. Moreover, although Akt1-and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3؊/؊ but not Akt1 ؊/؊ mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.While complex organisms grow toward determinate final sizes, there must be precise regulation within each tissue as well as coordination among organs to reach these final sizes (18,24). The regulation of both cell number and size contributes to the establishment of organ size, whereas cell number appears to be predominant in determining differences between species. Several factors, including circulating hormones and metabolites as well as cell-autonomous signaling cascades, control these processes (31). One of the key extracellular effectors determining organismal size is insulin-like growth factor 1 (IGF1). As demonstrated by genetic studies with mice, IGF1 is required for normal embryonic and postnatal growth (4,43,44,59). In addition, IGF1 controls the sizes of individual organs (43, 59). For example, normal brain growth requires IGF1 (6, 43), as IGF1-deficient brains are reduced in size secondary to a decrease in both cell number and cell size (6,15). Similarly, humans with IGF1 deficiency display severe growth retardation and suffer from mental retardation (75).In addition to extracellular factors, the intracellular signaling pathways determining growth are being uncovered. IGF1 acts through the type 1 IGF receptor to modulate an evolutionarily conserved pathway of molecules involved in the regulation of growth and metabolism (38,53). For many hormones, including IGF1 and insulin, binding to a receptor stimulates its protein tyrosine kinase activity, leading to the phosphorylation of scaffold proteins of the insulin receptor substrate (IRS) family. IRS proteins assemble complexes that include a number of potential signaling proteins, of which the lipid kinase phosphatidylinositol 3-kinase (PI3K) appears to be the most critical for the maintenance of cell size and proliferation (10). PI3K catalyzes the generation of phospha...