Endoplasmic Reticulum Stress Regulators : New Drug Targets for Parkinson's Disease

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http://hdl.handle.net/10138/335297

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Kovaleva , V & Saarma , M 2021 , ' Endoplasmic Reticulum Stress Regulators : New Drug Targets for Parkinson's Disease ' , Journal of Parkinson's disease , vol. 11 , no. s2 , pp. S219-S228 . https://doi.org/10.3233/jpd-212673

Title: Endoplasmic Reticulum Stress Regulators : New Drug Targets for Parkinson's Disease
Author: Kovaleva, Vera; Saarma, Mart
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2021
Language: eng
Number of pages: 10
Belongs to series: Journal of Parkinson's disease
ISSN: 1877-7171
URI: http://hdl.handle.net/10138/335297
Abstract: Parkinson's disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborization and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2+ dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2+ homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signaling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in an animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical animal models of PD. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.
Subject: 3112 Neurosciences
3124 Neurology and psychiatry
cerebral dopamine neurotrophic factor
endoplasmic reticulum stress
growth factors
mesencephalic astrocyte-derived neurotrophic factor
Parkinson's disease
unfolded protein response
ER-STRESS
NEUROTROPHIC FACTOR
DOWN-REGULATION
ALPHA-SYNUCLEIN
SUBSTANTIA-NIGRA
EXPERIMENTAL-MODELS
RAT MODEL
UNFOLDED-PROTEIN-RESPONSE
MIDBRAIN DOPAMINE NEURONS
CDNF PROTECTS
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