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Mol Neurodegener. 2017 Jan 25;12(1):11. doi: 10.1186/s13024-017-0154-3.

Therapeutic potential of autophagy-enhancing agents in Parkinson's disease.

Author information

1
Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam Neuroscience, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. t.moors@vumc.nl.
2
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
3
Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy, Amsterdam Neuroscience, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
4
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
5
Department of Medicine, Section of Neurology, University of Perugia, Perugia, Italy.
6
UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, Lille, F-59000, France.
7
Inserm, UMR-S 1172, Team "Early stages of Parkinson's disease", F-59000, Lille, France.

Abstract

Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson's Disease (PD). Genetic studies have identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn). As autophagy is one of the main systems involved in the proteolytic degradation of α-syn, pharmacological enhancement of autophagy may be an attractive strategy to combat α-syn aggregation in PD. Here, we review the potential of autophagy enhancement as disease-modifying therapy in PD based on preclinical evidence. In particular, we provide an overview of the molecular regulation of autophagy and targets for pharmacological modulation within the ALP. In experimental models, beneficial effects on multiple pathological processes involved in PD, including α-syn aggregation, cell death, oxidative stress and mitochondrial dysfunction, have been demonstrated using the autophagy enhancers rapamycin and lithium. However, selectivity of these agents is limited, while upstream ALP signaling proteins are involved in many other pathways than autophagy. Broad stimulation of autophagy may therefore cause a wide spectrum of dose-dependent side-effects, suggesting that its clinical applicability is limited. However, recently developed agents selectively targeting core ALP components, including Transcription Factor EB (TFEB), lysosomes, GCase as well as chaperone-mediated autophagy regulators, exert more specific effects on molecular pathogenetic processes causing PD. To conclude, the targeted manipulation of downstream ALP components, rather than broad autophagy stimulation, may be an attractive strategy for the development of novel pharmacological therapies in PD. Further characterization of dysfunctional autophagy in different stages and molecular subtypes of PD in combination with the clinical translation of downstream autophagy regulation offers exciting new avenues for future drug development.

PMID:
28122627
PMCID:
PMC5267440
DOI:
10.1186/s13024-017-0154-3
[Indexed for MEDLINE]
Free PMC Article

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