A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression

Abstract

Pathological modification of α-synuclein is believed to be an important event in pathogenesis of Parkinson’s disease and several other neurodegenerative diseases. In normal cells this protein has been linked to many intracellular processes and pathways. However, neither normal function of α-synuclein in neuronal and certain other types of cells nor its exact role in the disease pathogenesis is well understood, which is largely due to limitations of animal models used for studying this protein. We produced and validated several novel mouse lines for manipulating expression of the endogenous Snca gene coding for α-synuclein. These include a line for conditional Cre-recombinase-driven inactivation of the gene; a line for conditional Flp-driven restoration of a neo-cassete-blocked α-synuclein expression; a new line with a “clean” constituent knockout of the gene as well as a line carrying this knockout locus and Rosa26-stop-lacZ reporter locus linked at the same mouse chromosome 6. Altogether these lines represent a set of new useful tools for studies of α-synuclein normal function and the role of this protein in disease pathogenesis.

RETRACTED ARTICLE: Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

“…Moreover, Braak et al hypothesized that misfolded α-syn could be propagated from cell to cell similar to the pathological spreading of LB in sporadic PD, in which α-syn was converted into an abnormal aggregation [ 17 – 19 ]. This spreading pathology has been mimicked in experimental animals by injecting fibril α-syn and brain homogenates from transgenic mice or patients [ 20 – 22 ]. However, fibril α-syn is not a native protein of the brain and was produced in vitro after sonication [ 23 ].…”

Generation of mouse lines with conditionally or constitutively inactivated Snca gene and Rosa26-stop-lacZ reporter located in cis on the mouse chromosome 6

“…This genomic modification does not affect expression of neighboring genes, e.g. Mmrn1 (Ninkina et al 2015), which is a drawback for the knockout mice produced by Abeliovich et al Mice homozygous for this Cre-induced deletion, [ Snca − _Rosa26 wt / Snca − _Rosa26 wt ], were crossed with homozygous mice bearing Rosa26 - stop - lacZ cassette, [ Snca + _Rosa26 mod / Snca + _Rosa26 mod ], and resulting F1 offsprings of [ Snca + _Rosa26 mod / Snca − _Rosa26 wt ] genotype were intercrossed (Fig. 2a).…”

Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis

“…Generation of RPTEC-specific SNCA null mice. To generate RPTEC-specific SNCA null mice, SNCA flox mice [B6(Cg)-Snca tm1.1Vlb /J; JAX stock #025636] purchased from the Jackson Laboratory (Bar Harbor, ME) 58 were bred with a PEPCK Cre+ transgenic mice (Cre recombinase under the control of the phosphoenolpyruvate carboxykinase promoter 39 ) on a C57BL/6J background (kindly provided by Dr. Volker Haase, Vanderbilt University) 39 to yield PEPCK Cre+ -SNCA wt/flox progeny. The PEPCK Cre transgenic mice show~10-fold increase in PEPCK expression in renal proximal tubule 59 .…”