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      Reversing Parkinson Disease Model with in situ Converted Nigral Neurons


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          Parkinson disease is characterized by loss of dopamine neurons in the substantia nigra 1. Similar to other major neurodegenerative disorders, no disease-modifying treatment exists. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits 2. Herein we report an efficient single-step conversion of isolated mouse and human astrocytes into functional neurons by depleting the RNA binding protein PTB. Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes into new neurons that can innervate into endogenous neural circuits. Astrocytes in different brain regions are found to convert into different neuronal subtypes. Using a chemically induced model of Parkinson’s disease, we show conversion of midbrain astrocytes into dopaminergic neurons whose axons reconstruct the nigro-striatal circuit. Significantly, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. Similar disease phenotype reversal is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible new approach to treating neurodegeneration by replacing lost neurons.

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          Most cited references54

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          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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            Cutadapt removes adapter sequences from high-throughput sequencing reads

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              Parkinson disease

              Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.

                Author and article information

                19 May 2020
                24 June 2020
                June 2020
                24 December 2020
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                [1 ]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla CA 92093, USA
                [2 ]State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
                [3 ]MOE Key Lab of Medical Electrophysiology, ICR, Southwest Medical University, Luzhou 646000, China
                [4 ]Present address: Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China.
                [5 ]Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA
                [6 ]Present address: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
                [7 ]Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla CA 92093, USA
                [8 ]Department of Neurosciences and Center for Neural Circuits and Behavior, La Jolla CA 92093, USA
                [9 ]Institute of Genomic Medicine, University of California, San Diego, La Jolla CA 92093, USA
                Author notes


                H.Q. and X-D.F. designed the study. H.Q. performed astrocyte isolation, stereotaxic injection, immunocytochemistry, electrophysiological measurements, and behavior tests. J.H., Y.X. and F.M. contributed to AAV vector construction, immunoblotting, immunocytochemistry and independently characterized astrocyte conversion in vitro. F.M. also contributed to the performance of behavior tests. Z.L. and F.M. performed RNA-seq and data analysis. H.Q., X.Z., D. Z., and N.K.D. measured striatal dopamine levels. X.K and Z.Z recorded activity-induced dopamine release in live animals and on brain slices. S.F.D. supervised ASO design and testing. W.C.M. contributed to analysis and interpretation of neurological data. D.W.C. oversaw biochemical and immunocytochemistry experiments. R.M. independently showed that ASO-mediated suppression of PTB generated new neurons in wild-type mice. R.M. also checked all raw data and verified biological repeats of individual experiments (for details, see Supplementary Table 2). H.Q., S.F.D., W.C.M., D.W.C., and X-D.F. wrote the paper.

                Corresponding author: Xiang-Dong Fu, xdfu@ 123456ucsd.edu , Phone: 858-534-4937

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