Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons
Mazzulli JR, Zunke F, Tsunemi T, Toker NJ, Jeon S, Burbulla LF, Patnaik S, Sidransky E, Marugan JJ, Sue CM, Krainc D (2016)
Publication Type: Journal article
Publication year: 2016
Journal
Book Volume: 36
Pages Range: 7693-7706
Journal Issue: 29
DOI: 10.1523/JNEUROSCI.0628-16.2016
Abstract
Parkinson’s disease (PD) is characterized by the accumulation of α-synuclein (α-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing α -syn inclusions in PD. Recent data has indicated that loss-offunction mutations in the GBA1 gene that encodes lysosomal β-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to α -syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce α-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations,wefind that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological α-syn, regardless of the disease causing mutations. Importantly, the reduction of α-syn was sufficient to reverse downstream cellular pathologies induced by α-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce α-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies.
Authors with CRIS profile
Involved external institutions
Northwestern University
United States (USA) (US)
US National Institutes of Health (NIH)
United States (USA) (US)
National Human Genome Research Institute (NHGRI)
United States (USA) (US)
Massachusetts General Hospital
United States (USA) (US)
Royal North Shore Hospital (RNSH)
Australia (AU)
United States (USA) (US)
US National Institutes of Health (NIH)
United States (USA) (US)
National Human Genome Research Institute (NHGRI)
United States (USA) (US)
Massachusetts General Hospital
United States (USA) (US)
Royal North Shore Hospital (RNSH)
Australia (AU)
How to cite
APA:
Mazzulli, J.R., Zunke, F., Tsunemi, T., Toker, N.J., Jeon, S., Burbulla, L.F.,... Krainc, D. (2016). Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons. Journal of Neuroscience, 36(29), 7693-7706. https://dx.doi.org/10.1523/JNEUROSCI.0628-16.2016
MLA:
Mazzulli, Joseph R., et al. "Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons." Journal of Neuroscience 36.29 (2016): 7693-7706.
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