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Targeting alpha-synuclein-lipid interactions in preclinical Parkinson's disease models

Parkinson’s disease is caused by loss of dopaminergic neurons in significant part secondary to accumulation/aggregation of a protein called a-synuclein. New information has shown that this aggregation occurs, in part, through a-synuclein interactions with a lipid called glucocerebroside. NP003 regulates the production of glucocerebroside in a process predicted to interfere with a-synuclein aggregation and Parkinson’s disease pathogenesis. The current study will test NP003 in a Parkinson’s disease pre-clinical model where a-synuclein accumulation causes disease-like pathology.

Project Description:
We hypothesize that regulation of glucocerebroside metabolism can change a-synuclein aggregation and reduce the development of Parkinson’s disease. To test this, we will utilize the multidrug resistance glycoprotein-1 (MDR1) inhibitor, NP003, to reduce cellular glucocerebroside production. NP003 has been studied in normal humans and has been shown to be safe and effective at regulating production of glucocerebroside in pre-clinical models. For the Parkinson’s disease study NP003 will be administered to an a-synuclein overexpressing model that develops robust neuropathology and severe motor deficits.  These studies will test whether:  (i) lipid metabolism contributes to the onset and development of a-synuclein pathology and related neurologic dysfunction and (ii) regulation of this pathway by NP003 can impact the neurological injury and behavioral impairments in the model.

Relevance to Diagnosis/Treatment of Parkinson’s Disease
Regulation of a-synuclein-lipid interactions through NP003-mediated regulation of glucocerebroside metabolism is a novel target mechanism for treatment of Parkinson’s and other neurodegenerative diseases involving a-synuclein pathology.  If successful, these studies will demonstrate pre-clinical efficacy of a novel, orally-administered compound that has been tested in humans and deemed safe in nine clinical trials.

Anticipated Outcome:
The only approved therapies for Parkinson’s disease target alleviation of symptoms, not disease modification. The approach being taken in the current study will test whether regulation of glucocerebroside associated aggregation of a-synuclein through NP003 administration may be effective at modifying the Parkinson’s disease process. This approach, if successful, will suggest a new pathway for study of Parkinson’s disease pathogenesis and, at the same time, presents a novel, non-toxic drug approach to this pathway.

Final Outcome

Per our experimental design, 7-8 animals per group (wild type [WT] treated, WT control, ASO treated, ASO control) were dosed with NP003 or saline intraperitoneally three times a week for a period of 5-6 months. In life measurements included weight and motor behavior. Post-sacrifice measurements included biochemistry and histology of select tissues.

There were no significant differences in weights between the treatment and control groups of animals at the time of sacrifice.  NP003 administration to ASO mice, as compared with saline-treated ASO mice, was associated with a delay in onset of motor impairment with a positive trend noted at 100 days and significant preservation of gait noted at 200 days of study. However, administration of NP003 had no measureable effects on normal WT mouse motor behavior. The WT animals showed no disease-associated abnormalities in this experiment.

Preliminary data from the biochemical assessments of a-synuclein in different brain regions from the experimental mice suggest that NP003 impacted a-synuclein cellular load and distribution in the ASO mice.  In WT mice, no significant difference in a-synuclein immunoreactivities was detected between the NP003- vs. saline-treated groups.

A decrease in a-synuclein cell body localization was detected in cortex and spinal cord of ASO mice administered NP003 vs. saline. Very little difference was noted in WT mice administered the drug vs. vehicle.

Although the data from this study are pilot in nature utilizing very small numbers of animals, the results suggest that in this study with this line of a-synuclein overexpressing mice, NP003 administration was associated with a) maintenance of motor function potentially related to a-synuclein accumulation and b) region-specific alterations in accumulation and/or aggregation of a-synuclein. 


  • Vidhya Gopalakrishnan, PhD

    Palo Alto, CA United States

  • Amy Manning-Bog, PhD

    Menlo Park, CA United States

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