Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction

Ginns, Edward I.; Mak, Sally K.; Ko, Novie; Karlgren, Juliane; Akbarian, Schahram; Chou, Vivian P.; Guo, Yin; Lim, Arlene; Samuelsson, Steven J.; LaMarca, M.; Vazquez-DeRose, Jacqueline; Manning-Bog, Amy

doi:10.1016/j.ymgme.2013.12.003

Cited by 96 publications

(86 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, we expect that examination of CBE-treated mice at a later time point may have revealed nigrostriatal degeneration. This is further supported by recent data demonstrating that mice treated with a different, subchronic dosing regimen of CBE resulted in α-synuclein accumulation and reduced striatal dopamine release (20), indicative of dysfunction in the nigrostriatal dopamine system.…”

Section: Gcase Inhibition Induced Widespread Neuroinflammation and Cosupporting

confidence: 67%

“…This is supported by data demonstrating that overexpression of α-synuclein can disrupt neurotransmitter release by disrupting synaptic vesicle recycling prior to detectable neuropathology changes (41). Moreover, daily dosing of CBE to mice can disrupt dopamine neurotransmission by impairing striatal dopamine release and causing a reduction in postsynaptic density size (20). Synaptic accumulation of -synuclein is associated with redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2 (18).…”

Section: Antioxidants and Redox Signalingmentioning

confidence: 90%

See 1 more Smart Citation

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

Rocha

Smith

Park

et al. 2015

Antioxidants & Redox Signaling

125

101

View full text Add to dashboard Cite

Aims: Loss-of-function mutations in GBA1, which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of α-synuclein in PD. In this report we used conduritol-β-epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity in vivo, and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including α-synucleinopathy, and neurodegeneration. Results: Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble α-synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration. Innovation: A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of α-synucleinopathy. Conclusions: These data reveal a link between reduced glucocerebrosidase and the development of α-synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce α-synucleinopathy in PD and related disorders. Antioxid. Redox Signal. 23, 550–564.

show abstract

Section: Gcase Inhibition Induced Widespread Neuroinflammation and Cosupporting

confidence: 67%

Section: Antioxidants and Redox Signalingmentioning

confidence: 90%

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

Rocha

Smith

Park

et al. 2015

Antioxidants & Redox Signaling

125

101

View full text Add to dashboard Cite

show abstract

“…Moreover, this molecular study is in line with the contention that both mutated and wild type glucocerebrosidase can induce Parkinson-like synucleinopathy [49]. In a functional knockdown model of Gaucher disease, there was evidence that over-expression of mutated glucocerebrosidase significantly increased a-synuclein levels while at the same time decreasing evoked dopamine release [50]. The issues that are indirectly raised by these data relate to recognition that the mere presence of mutated glucocerebrosidase is inimical to neurological integrity but also that there is putatively accelerated evolution of neurological co-morbidities because of induction of biochemical changes and neuroinflammation.…”

Section: A Genetic Study Of A-synuclein In Gaucher Diseasesupporting

confidence: 82%

The emergence of Parkinson disease among patients with Gaucher disease

Elstein

Alcalay

Zimran

2015

Best Practice & Research Clinical Endocrinology & Metab

View full text Add to dashboard Cite

“…Several independent groups have now reported the presence of asynuclein accumulation in the brains of mouse models of Gaucher disease carrying different mutations (Cullen et al, 2011;Fishbein et al, 2014;Ginns et al, 2014;Sardi et al, 2011;Xu et al, 2010Xu et al, , 2014. The initial insult caused by the lipid and a-synuclein accumulation can then progress to develop secondary neuroinflammatory pathology, mitochondrial dysfunction or a more profound proteinopathy (Ginns et al, 2014;Sardi et al, 2013;Xu et al, 2014). Finally, studies have shown that increasing glucocerebrosidase levels can modulate a-synuclein accumulation.…”

Section: Reduced Glucocerebrosidase Increases A-synuclein Levelsmentioning

confidence: 99%

“…Remarkably, a-synuclein is localized to lipid rafts in neuronal cells (Fortin et al, 2004), and glucosylceramide has been described to directly promote a-synuclein oligomerization (Mazzulli et al, 2011). Therefore, it is speculated that lipid changes induced by partial glucocerebrosidase deficiency may alter the interaction between lipid microdomains and asynuclein, which might, in turn, lead to synaptic dysfunction and selective neuronal demise Ginns et al, 2014).…”

Section: Glucocerebrosidase Decline and Lipid Alterationsmentioning

confidence: 99%

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Sardi¹,

Cheng²,

Shihabuddin³

2015

Progress in Neurobiology

View full text Add to dashboard Cite

Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related synucleinopathies, and potentially, for non-GBA1-associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.

show abstract

Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction

Cited by 96 publications

References 92 publications

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

The emergence of Parkinson disease among patients with Gaucher disease

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Contact Info

Product

Resources

About