Neuropathology in Mice Expressing Mouse Alpha-Synuclein

Abstract

α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occured in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

“…The presence of increased levels of endogenous α-syn mRNA and protein levels in LIMP-2 −/− mice backcrossed into C57/BL6-N mice led to severe neurological deficits and premature death in contrast to LIMP-2-deficient mice bred in the α-syn-deficient background, clearly suggesting a link between disease severity and α-syn dosage. A dosage relationship between α-syn and disease progression is consistent with recent reports showing that transgenic overexpression of murine WT α-syn exacerbates the neurological phenotype (28,29). These reports are also in agreement with some cases of familial PD, where duplications or triplications of the SNCA gene lead to Lewy pathology and disease onset that correlates with α-syn expression (30).…”

Remodeling of Lipid Vesicles into Cylindrical Micelles by α-Synuclein in an Extended α-Helical Conformation

“…However, there have been reports of thin filamentous structures in neural tissues of humans and a mouse model that are ␣S-positive according to immuno-gold EM with anti-␣S antibodies (68,69). The present findings raise the possibility that they may represent cylindrical micelles instead of or as well as amyloid fibrils.…”

Novel One-step Immunoassays to Quantify α-Synuclein

“…Food and water were available ad libitum. Thy1-human ␣-synuclein (A53T) transgenic mice (27,28) were genotyped using primers HP45 (5Ј-ACA CCC CTA AAG CAT ACA GTC AGA CC-3Ј) and HP42 (5Ј-TGG GCA CAT TGG AAC TGA GCA CTT-3Ј). Transgenic mice were kept in C57BL/6 background.…”