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Published on: June 18, 2018
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A GCase chaperone improves motor function in a mouse model of synucleinopathy
Franziska Richter1, Sheila M Fleming, Melanie Watson
1The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095-1769, USA.
Summary
Targeting acid-β-glucosidase (GCase) with pharmacological chaperones may treat Parkinson's disease (PD). This study shows AT2101 improved motor function and reduced α-synuclein in mice, suggesting a potential therapy for sporadic PD.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Acid-β-glucosidase (GCase) mutations are a frequent genetic risk factor for Parkinson's disease (PD).
- Reduced GCase activity is linked to α-synuclein accumulation, a key feature of PD and other synucleinopathies.
- The therapeutic potential of targeting GCase in sporadic PD without GCase mutations remains unclear.
Purpose of the Study:
- To investigate if enhancing wild-type GCase activity, stability, and trafficking using the pharmacological chaperone AT2101 benefits synucleinopathies.
- To evaluate the efficacy of AT2101 in a mouse model of synucleinopathy.
Main Methods:
- Administration of AT2101 (afegostat-tartrate) orally to mice overexpressing human wild-type α-synuclein (Thy1-aSyn mice) for 4 months.
- Assessment of motor and non-motor functions, microglial inflammatory response, α-synuclein levels, and aggregate size.
Main Results:
- AT2101 treatment improved motor and non-motor functions in Thy1-aSyn mice.
- The treatment abolished microglial inflammatory response in the substantia nigra.
- Reduced α-synuclein immunoreactivity and small aggregates were observed, with an increase in large aggregates.
Conclusions:
- Pharmacological chaperones targeting GCase, such as AT2101, show therapeutic potential for sporadic PD and other synucleinopathies.
- This approach may be beneficial even in the absence of glucocerebrosidase mutations.
- Further investigation into GCase-targeting chaperones is warranted for PD treatment.
