Development of targeted therapies for Parkinson's disease and related synucleinopathies

Sybertz, Edmund J.; Krainc, Dimitri

doi:10.1194/jlr.r047381

Cited by 18 publications

(21 citation statements)

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“…The same strategy was effective in diminishing levels of soluble α‐Syn in an A53T α‐Syn transgenic mouse model, although insoluble α‐Syn was not affected . Inhibition of glucosylceramide synthetase with small molecules to prevent substrate buildup represents another possible therapeutic approach, provided that the compound can gain access to the CNS . Another approach to enhance GCase activity is by facilitating GCase translocation from the ER to the lysosome, a process inhibited by aberrant α‐Syn species.…”

Section: The Future Of Therapies Counteracting α‐Syn Pathology: Focusmentioning

confidence: 99%

Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

2016

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Evidence from human postmortem material, transgenic mice, and cellular/animal models of PD link alpha-synuclein accumulation to alterations in the autophagy lysosomal pathway. Conversely, alpha-synuclein mutations related to PD pathogenesis, as well as post-translational modifications of the wild-type protein, result in the generation of aberrant species that may impair further the function of the autophagy lysosomal pathway, thus generating a vicious cycle leading to neuronal death. Moreover, PD-linked mutations in lysosomal-related genes, such as glucocerebrosidase, have been also shown to contribute to alpha-synuclein accumulation and related toxicity, indicating that lysosomal dysfunction may, in part, account for the neurodegeneration observed in synucleinopathies. In the current review, we summarize findings related to the inter-relationship between alpha-synuclein and lysosomal proteolytic pathways, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysosomal pathway to counteract alpha-synuclein-mediated neurotoxicity in vivo. Pinpointing the factors that regulate alpha-synuclein association to the lysosome may represent potential targets for therapeutic interventions in PD and related synucleinopathies.

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Section: The Future Of Therapies Counteracting α‐Syn Pathology: Focusmentioning

confidence: 99%

Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

2016

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“…Accumulation of β-glucosylceramide, the substrate of GCase, in neurons promotes the formation of α-synuclein oligomers, which are considered toxic in PD 12 . Enhancement of GCase activity is thought to be a potential therapeutic strategy for GCase-associated synucleinopathies, including PD 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators

et al. 2016

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Gaucher’s disease is a common genetic disease caused by mutations in the β-glucocerebrosidase (GBA1) gene that have been also linked to increased risk of Parkinson’s disease and Lewy Body Dementia. Stabilization of misfolded mutant β-glucocerebrosidase (GCase) represents an important therapeutic strategy in synucleinopathies. Here we report a novel class of GCase quinazoline inhibitors, obtained in a high throughput screening, with moderate potency against wild-type GCase. Rational design and a SAR study of this class of compounds led to a new series of quinazoline derivatives with single digit nanomolar potency. These compounds were shown to selectively stabilize GCase when compared to other lysosomal enzymes and to increase N370S mutant GCase protein concentration and activity in cell assays. To the best of our knowledge, these molecules are the most potent non-iminosugar GCase inhibitors to date that may prove useful for future mechanistic studies and therapeutic approaches in Gaucher’s and Parkinson’s diseases.

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“…13 In fact, there may be overlap between lysosomal storage and PD, with implications for other neuro degenerations of complex etiology. 14 Systemic delivery for neuro degenerative diseases has clear theoretical advantages over approaches that require delivery directly into the central nervous system. Depending on the method of delivery, the drug may also be able to effect important corrections in the periphery that can feed back on the brain syndrome.…”

Section: Engineered Antibody Therapies Coming Of Age For Aging Brainsmentioning

confidence: 99%

“…13 Not all of the phase II and III clinical trials have been conclusively evaluated (http://www.ptcbio.com/ clinical_trials), but it seems that the drug has a good safety profile and improves some symptoms, 13 although not all patients benefit from the treatment. 14 Presumably, as delineated above, future therapies must be applied on an individualized basis, selecting patients with optimal mutation and PTC recognition constellations that respond to a particular drug and its mode of action. Of note, in the study by Cogan et al, 3 all DEB cells and expression constructs carrying COL7A1 nonsense mutations were refractory to PTC124 treatment.…”

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confidence: 99%

Engineered Antibody Therapies Coming of Age for Aging Brains

Messer

2014

Molecular Therapy

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Development of targeted therapies for Parkinson's disease and related synucleinopathies

Cited by 18 publications

References 79 publications

Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators

Engineered Antibody Therapies Coming of Age for Aging Brains

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