Spinal muscular atrophy (SMA) is one of the most common inherited forms of neurological disease leading to infant mortality. Patients exhibit selective loss of lower motor neurons resulting in muscle weakness, paralysis, and often death. Although patient fibroblasts have been used extensively to study SMA, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem (iPS) cells from skin fibroblast samples taken from a child with SMA. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show human iPS cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen novel drug compounds, and develop new therapies.Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder caused by mutations in the survival motor neuron 1 gene (SMN1) significantly reducing SMN protein expression 1, 2 and resulting in the selective degeneration of lower α-motor neurons 3 . Clinically, patients with SMA 1 typically show symptoms at 6 months of age and die by age 2 4 . The SMN2 gene is an almost identical copy of SMN1 except that SMN2 has a single nucleotide difference that results in only 10% of full-length protein being produced and high levels of a truncated, unstable protein lacking exon 7 (SMNΔ7) 5 . However, patients with multiple copies of SMN2 produce more full-length protein and have a less severe phenotype 6 . While current model systems using worms, flies, or mice have provided invaluable data concerning the genetic cause of SMA, mechanisms of motor neuron death, and potential drug therapies 7 , they have Correspondence: Reprints and permissions information is available at npg.nature.com/reprintsandpermissions Correspondence should be addressed to ADE (ebert@waisman.wisc.edu) or CNS (cnsvendsen@wisc.edu). Requests for material should be addressed to CNS. Contributions: ADE participated in all aspects and prepared the manuscript; JY generated and aided in characterization of iPS-SMA and iPS-WT clones; FR, VBM, and CLL performed SMN analysis and manuscript preparation; JAT participated in the generation of the iPS clones; CNS conceived the project and participated in planning, data analysis, and manuscript preparation. The authors declare no competing financial interest.Supplementary Information accompanies the paper on www.nature.com/nature. A schematic outlining the main results is included as Supplementary Figure 1.

Reactive astrocytes adjacent to a forebrain stab injury were selectively ablated in adult mice expressing HSV-TK from the Gfap promoter by treatment with ganciclovir. Injured tissue that was depleted of GFAP-positive astrocytes exhibited (1) a prolonged 25-fold increase in infiltration of CD45-positive leukocytes, including ultrastructurally identified monocytes, macrophages, neutrophils, and lymphocytes, (2) failure of blood-brain barrier (BBB) repair, (3) substantial neuronal degeneration that could be attenuated by chronic glutamate receptor blockade, and (4) a pronounced increase in local neurite outgrowth. These findings show that genetic targeting can be used to ablate scar-forming astrocytes and demonstrate roles for astrocytes in regulating leukocyte trafficking, repairing the BBB, protecting neurons, and restricting nerve fiber growth after injury in the adult central nervous system.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. Here, we report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS motor neurons. Repeat-containing RNA foci co-localized with hnRNPA1 and Pur-α, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides (ASOs) targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.