Over expression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice

Meike Diepenbroek, Nicolas Casadei, Hakan Esmer, Takaomi C. Saido, Jiro Takano, Philipp J. Kahle, Ralph A. Nixon, Mala V. Rao, Ronald Melki, Laura Pieri, Stefan Helling, Katrin Marcus, Rejko Krueger, Eliezer Masliah, Olaf Riess*, Silke Nuber

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

90 Citations (Scopus)

Abstract

Lewy bodies, a pathological hallmark of Parkinson's disease (PD), contain aggregated alpha-synuclein (αSyn), which is found in several modified forms and can be discovered phosphorylated, ubiquitinated and truncated. Aggregation-prone truncated species of αSyn caused by aberrant cleavage of this fibrillogenic protein are hypothesized to participate in its sequestration into inclusions subsequently leading to synaptic dysfunction and neuronal death. Here, we investigated the role of calpain cleavage of α Syn in vivo by generating two opposing mouse models. We crossed in to human [A30P]αSyn transgenic (i) mice deficient for calpastatin, a calpain-specific inhibitor, thus enhancing calpain activity (SynCAST(2)) and (ii) mice over expressing human calpastatin leading to reduced calpain activity (SynCAST(1)). As anticipated, a reduced calpain activity led to a decreased number of α Syn-positive aggregates, whereas loss of calpastatin led to increased truncation of αSyn in SynCAST(2). Further more, over expression of calpastatin decreased astrogliosis and the calpaindependent degradation of synaptic proteins, potentially ameliorating the observed neuropathology in [A30P]αSyn and SynCAST(+) mice. Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD.

Original languageEnglish
Article numberddu112
Pages (from-to)3975-3989
Number of pages15
JournalHuman Molecular Genetics
Volume23
Issue number15
DOIs
Publication statusPublished - Aug 2014
Externally publishedYes

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