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Schneider, B. L.

Publications and source records attributed to Schneider, B. L..

3 recordsLinked to original sources
bioRxiv2021

Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and non-cell-autonomous mechanisms lead to the selective degeneration of motoneurons. Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of fast-fatigable motoneurons until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIb muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/re-innervation events. The transcriptome profiling of spinal cord motoneurons shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes provides therapeutic effects enhancing motoneuron plasticity and improving neuromuscular function in ALS mice.

neuroscience↗
bioRxiv2020

PARKIN REGULATES DRUG TAKING-BEHAVIOR IN RAT MODEL OF METHAMPHETAMINE USE DISORDER

There is no FDA-approved medication for Methamphetamine (METH) Use Disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH Use Disorder. PARKIN knockout, PARKIN-overexpressing and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying "resilience" or vulnerability to METH Use Disorder, and identify PARKIN as a novel potential drug target to treat heavy use of METH.

neuroscience↗
bioRxiv2020

A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

Background & aims Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and death in children. SMA patients are more susceptible to dyslipidemia as well as liver steatosis, features reproduced in SMA mouse models. As current pre-clinical models of NAFLD are invariably imperfect and generally take a long time to develop, the rapid development of liver steatosis in SMA mice provides a means to identify molecular markers of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether Smn2B/- mice, a model of severe SMA, display typical features of NAFLD/non-alcoholic steatohepatitis (NASH).Methods Biochemical, histological, electron microscopy, proteomic, and high-resolution respirometry were used.Results The Smn2B/- mice develop steatohepatitis early in life. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in impaired hepatic function including alterations in protein output, complement, coagulation, iron homeostasis, and IGF-1 metabolism. The steatohepatitis is reversible by AAV9-SMN gene therapy. The NAFLD phenotype is likely due to non-esterified fatty acid (NEFA) overload from peripheral lipolysis, subsequent to hyperglucagonemia compounded by reduced muscle use. Mitochondrial β-oxidation contributed to hepatic damage as we observed enhanced hepatic mitochondrial β-oxidation and reactive oxygen species production. Hepatic mitochondrial content, however, was decreased. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight due to their neurological condition, develop hypoglycemia and do not develop hepatic fibrosis.Conclusion The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.Competing Interest StatementMarc-Olivier Deguise received honoraria and travel accommodations from Biogen for speaking engagements at the SMA Summit 2018 held in Montreal, Canada and SMA Academy 2019 held in Toronto, Canada. Rashmi Kothary received honoraria and travel accommodations from Roche as an invited speaker at their global and national board meetings in 2019. RK and the Ottawa Hospital Research Institute have a licensing agreement with Biogen for the Smn2B/- mouse model. Thomas H. Gillingwater has served on global and UK advisory boards for Roche. These COI are outside the scope of this study. All other authors have no competing interests to declare.List of abbreviationsAGCautomatic gain controlALPalkaline phosphataseALTalanine aminotransferaseASTaspartate aminotransferaseBaxBCL2 associated X proteinDAVIDThe Database for Annotation, Visualization and Integrated DiscoveryESEnrichment ScoreFasRFas receptorH&EHematoxylin & eosinHFDhigh fat dietIGF-1insulin-like growth factor 1IGFbp1insulin like growth factor binding protein 1IGF1Rinsulin like growth factor 1 receptorigfalsinsulin like growth factor binding protein acid labile subunitIPAingenuity pathway analysisMCDmethionine and choline deficient dietMCLMarkov Clustering AlgorithmNAFLDnon-alcoholic fatty liver diseaseNASHnon-alcoholic steatohepatitisNEFAnon-esterified fatty acidPpostnatal dayp21cyclin dependent kinase inhibitor 1Ap53tumor protein p53PASPeriodic acid-SchiffSMAspinal muscular atrophySMN1Survival motor neuron 1TMTTandem Mass TaggingTNFR1TNF receptor superfamily member 1AView Full Text

pathology↗