, 2011), as is seen in PD brain pathology. In the homozygous state, GBA mutations are associated with Gaucher’s disease, with severe lysosomal dysfunction typically early in life (Mazzulli et al., 2011). As expected, iPSC derived neurons that harbor triplication of the αSyn locus display similarly increased accumulation of αSyn protein ( Byers et al.,

2011). Regulation of αSyn gene expression is species specific, and appears to be modified both in familial and sporadic PD brain ( Rhinn et al., 2012); thus in vitro human neuronal models may prove to be particularly useful. ALS is characterized by a progressive loss of motor neurons in the spinal cord, leading to difficulty with movement and breathing. Rare Osimertinib Selleckchem MLN0128 familial forms of ALS have been unambiguously associated with mutations in superoxide dismutase-1 (SOD1), transactive response DNA-binding 43 (TDP-43), fused in sarcoma (FUS), C9orf72, and approximately

a dozen other genes (Ferraiuolo et al., 2011). A common theme in the context of several of these familial forms—including mutant forms of SOD1, TDP-43, FUS, and C9orf72—is the formation of cytoplasmic aggregates (Ash et al., 2013, Da Cruz and Cleveland, 2011 and Mori et al., 2013). Furthermore, TDP-43 aggregates are found in the majority of nonfamilial “sporadic” ALS cases even in the absence of known mutations, supporting PD184352 (CI-1040) the idea that common mechanisms underlie the familial and sporadic forms. Cytoplasmic TDP-43 aggregates are typically seen in neurons and astrocytes along with concurrent “clearing” of the normal nuclear localization of TDP-43, and this has opened the possibility that loss of nuclear TDP-43 function, as well as aggregation, may play a role in pathology. Model organism studies, from mice to yeast, have brought significant insight into the role of genes such as TDP-43 in vivo, but questions persist about the specific mechanism of action in the context of human motor neurons. For instance, the relative importance of protein aggregates, nuclear

clearing, and the nonautonomous impact of astroglial pathology on motor neuron loss ( Da Cruz and Cleveland, 2011) is unclear. Initial analyses of iPSC-derived spinal motor neurons with mutations in TDP-43 have reported evidence of reduced motor neuron survival in vitro, particularly in the context of an oxidative toxin, arsenite, and accumulation of TDP-43 ( Bilican et al., 2012 and Egawa et al., 2012). A critical point is that these studies did not include validation using a “rescue” approach or cohorts of sufficient size for a statistical analysis, both of which are essential. A cohort of iPSC-derived motor neuron cultures that harbor ALS-associated mutations in SOD1 has been generated ( Boulting et al.