Abstract
α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/− transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/− transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology.
Highlights
Amid the group of neurodegenerative diseases known as α-synucleinopathies, characterized by the formation of aberrant α-synuclein pathological inclusions, multiple system atrophy (MSA) represents a unique entity
Induction of Central nervous system (CNS) αS inclusion pathology following the direct neonatal mouse brain injection of preformed αS fibrils in nTg and M20+/− mice was previously evaluated by our laboratory for its potential as a high throughput screening method for study of αS pathogenesis using fibrils comprised of recombinant in vitro polymerized human αS [37]
As immunohistochemical analysis revealed the induction of αS pathology only in the M83+/− mice, we utilized an additional cohort of M83+/− mice injected at neonatal day 0 with preformed wild type (WT) or A53T αS fibrils that were aged to 4 months old, the equivalent of 120 days post injection used in previous injections of adult mice [32, 33, 39], for comparative
Summary
Amid the group of neurodegenerative diseases known as α-synucleinopathies, characterized by the formation of aberrant α-synuclein (αS) pathological inclusions, multiple system atrophy (MSA) represents a unique entity. Similar to authentic prion disease driven by the prion protein, PrP, the concept of different strains of aggregated αS is emerging, in which distinct forms of misfolded αS, exhibiting different structural and biophysical properties, can produce distinct disease phenotypes [5, 27]. This αS strain model represents a compelling concept when applied to MSA, as it may provide an explanation for the idiosyncratic role of GCIs in the pathophysiology of this disease. Previous investigations utilizing mouse models of seeding pathology through intracerebral injections with brain tissue samples derived from human patients with either PD or MSA have shown MSA to be uniquely capable of inducing pathology [30]
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