Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Abstract

The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.ver the past two decades, studies stimulated by the discovery of genetic mutations occurring in familial Parkinson's disease (PD) have generated a number of hypotheses concerning potential mechanisms of PD pathogenesis. Nonetheless, the causes and mechanism of sporadic PD, which constitutes the majority of cases, remain unknown.Before the genetic discoveries, epidemiologic evidence suggested environmental toxins, traumatic brain injury, and viral infection as potential causes of idiopathic PD (1-7). All of these insults could cause neural inflammation, a common feature of PD brains; however, whether neural inflammation contributes to the etiology of the disease or is part of its effect remained unclear. Suggestive evidence indicating the involvement of inflammation in the pathogenesis of PD emerged after an outbreak of encephalitis lethargica following the 1918 influenza pandemic, which killed approximately 1 million people and left many survivors with postencephalitic Parkinsonism (PEP). Affected persons presented with cardinal symptoms of typical Parkinson's disease, including stooped posture, masklike faces, muscular rigidity, and tremorous extremities. Contemporary cases of viral infection-associated Parkinsonism are rare, but both epidemiology and patient case studies indicate that infection-associated PD still occurs today (8-10).The role of viral infection in the pathogenesis of PD has been a controversial subject for more than 50 years. Proponents have pointed out the known close temporal association between infection and PEP, whereas opponents have cited studies that failed to find any viral remnants in the brains of affected patients. Moreover, there were no known routes for peripheral viral migration into the central nervous system (CNS). Recently, R. Smey...

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

“…Interestingly, the inflammatory protease caspase-1 cleaves α-syn at Asp121, promoting its aggregation into amyloid fibrils similar to those previously found both in vitro and in vivo (16). In turn, the caspase-1 inhibitor prodrug VX-765 decreases α-syn truncation and aggregation in vitro and rescues cells from α-syn-induced toxicity (16). Therefore, VX-765 could exert neuroprotective effects on MSA pathogenesis by reducing α-syn cleavage, hence limiting its toxicity and its ability to form aggregates.…”

“…Accordingly, inhibiting α-syn truncation could alter the disease course in MSA (and other synucleinopathies) (15) by decreasing α-syn oligomerization and aggregation. Interestingly, the inflammatory protease caspase-1 cleaves α-syn at Asp121, promoting its aggregation into amyloid fibrils similar to those previously found both in vitro and in vivo (16). In turn, the caspase-1 inhibitor prodrug VX-765 decreases α-syn truncation and aggregation in vitro and rescues cells from α-syn-induced toxicity (16).…”

Caspase-1 clipping causes complications for α-synuclein

“…However, these rodent residues are uncharged, so their role in interactions with the positively charged N terminus is less clear. Similarly, changing the negatively charged aspartic acid at position 121 to a negatively charged glutamic acid abolished caspase-1 cleavage in vitro but induced toxicity in cells (1). In addition, C-terminal αSyn interaction partners or posttranslational modifications could act as steric protectants (Fig.…”

“…Scientists have begun identifying factors that may initiate or accelerate αSyn aggregation and how this process relates to progressive impairment of neuronal structure and function. In PNAS, companion papers by Wang et al (1) and Bassil et al (2) establish a compelling link between the accumulation of C-terminally truncated forms of αSyn created by caspase-1 and cellular dysfunction in culture and in vivo, all potentially initiated by inflammatory insults.…”

Combating Parkinson’s disease-associated toxicity by modulating proteostasis

“…α-Synuclein is a small protein (140 residues) whose mutation is associated with disease pathogenesis, and it is the main protein found in Lewy bodies of Parkinson's disease brains (16). Although the mechanism of α-synuclein-associated toxicity is still unclear, it has been shown that its disease-associated mutants are aggregation-prone and its aggregates are associated with neuronal toxicity (17,18). LRRK2 is a large (2,527 amino acids) multidomain protein whose mutation is a common cause of Parkinson's disease (19).…”