Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons

Joe Mazzulli, Friederike Zunke, Taiji Tsunemi, Nicholas J. Toker, Sohee Jeon, Lena Burbulla, Samarjit Patnaik, Ellen Sidransky, Juan J. Marugan, Carolyn M. Sue, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7693-7706
Number of pages14
JournalJournal of Neuroscience
Volume36
Issue number29
DOIs
StatePublished - Jul 20 2016

Fingerprint

Synucleins
Glucosylceramidase
Mesencephalon
Neurons
Parkinson Disease
Hydrolases
Mutation
Lewy Bodies
Induced Pluripotent Stem Cells
Dopaminergic Neurons
Lysosomes
Nervous System
Therapeutics
Pathology

Keywords

  • Glucocerebrosidase
  • Induced pluripotent stem cells
  • Lysosomes
  • Parkinson’s disease
  • Synucleinopathy
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mazzulli, Joe ; Zunke, Friederike ; Tsunemi, Taiji ; Toker, Nicholas J. ; Jeon, Sohee ; Burbulla, Lena ; Patnaik, Samarjit ; Sidransky, Ellen ; Marugan, Juan J. ; Sue, Carolyn M. ; Krainc, Dimitri. / Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 29. pp. 7693-7706.
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Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons. / Mazzulli, Joe; Zunke, Friederike; Tsunemi, Taiji; Toker, Nicholas J.; Jeon, Sohee; Burbulla, Lena; Patnaik, Samarjit; Sidransky, Ellen; Marugan, Juan J.; Sue, Carolyn M.; Krainc, Dimitri.

In: Journal of Neuroscience, Vol. 36, No. 29, 20.07.2016, p. 7693-7706.

Research output: Contribution to journalArticle

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T1 - Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons

AU - Mazzulli, Joe

AU - Zunke, Friederike

AU - Tsunemi, Taiji

AU - Toker, Nicholas J.

AU - Jeon, Sohee

AU - Burbulla, Lena

AU - Patnaik, Samarjit

AU - Sidransky, Ellen

AU - Marugan, Juan J.

AU - Sue, Carolyn M.

AU - Krainc, Dimitri

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AB - 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.

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