Dataset Information

Induction of CNS ?-synuclein pathology by fibrillar and non-amyloidogenic recombinant ?-synuclein.

ABSTRACT:

Background

?-Synuclein (?S) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson's disease. Aberrant aggregation of ?S also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of ?S pathology by a single intracerebral injection of exogenous amyloidogenic ?S in adult non-transgenic and transgenic mice expressing human ?S. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with ?S.

Results

In non-transgenic mice, we observed limited induction of neuronal ?S inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human ?S. More robust inclusion pathology was induced in transgenic mice expressing wild-type human ?S (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (?71-82) deletion protein of ?S was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic ?S demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without ?S pathological inclusions implicating this mechanism in aggregate formation.

Conclusions

The finding that a non-amyloidogenic ?71-82 ?S can induce pathology calls into question the simple interpretation that exogenous ?S catalyzes aggregation and spread of intracellular ?S pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of ?S pathology.

SUBMITTER: Sacino AN

PROVIDER: S-EPMC3893388 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein.

Sacino Amanda N AN Brooks Mieu M McGarvey Nicholas H NH McKinney Alex B AB Thomas Michael A MA Levites Yona Y Ran Yong Y Golde Todd E TE Giasson Benoit I BI

Acta neuropathologica communications 20130717

<h4>Background</h4>α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson's disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further ...[more]

PMID: 24252149

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