Chaperone therapy: protective against Parkinson's disease?

Inpharma 1326 - 23 Feb 2002 Chaperone therapy: protective against Parkinson’s disease? Augmentation of chaperone stress pathways may be a novel and effective way of ameliorating the toxicity associated with α-synuclein that is observed in Parkinson’s disease (PD) and several other human neurodegenerative disorders, report researchers from the US. 1 They evaluated the loss of dopaminergic neurons associated with the expression of α-synuclein in Drosophila models of PD. These models expressed wild- type human α-synuclein, or the two mutant forms pathogenic for familial PD. Hsp70 prevents neuronal loss Expression of either wild-type or mutant α-synuclein in the Drosophila models led to a marked loss of dopaminergic neurons in the dorsomedial cluster. In addition, impairing the activity of the endogenous chaperone Hsc4 in the Drosophila models led to a more rapid loss of neurons. However, coexpression of a human chaperone, heat shock protein (Hsp)70, with α-synuclein completely prevented the loss of dopaminergic neurons seen in Drosophila models expressing α-synuclein alone. The researchers comment that the protection was specific to Hsp70 as coexpression of a control protein (β- galactosidase) did not prevent α-synuclein associated neuronal loss. Although human Hsp70 prevented the loss of dopaminergic neurons in the Drosophila models, it did not prevent the formation of protein inclusions that are analogous to Lewy bodies and Lewy neurites, despite being present in the inclusions. These data suggest that Hsp70 may be a critical part of the arsenal that prevents α-synuclein associated toxicity, or alternatively, the expression of α-synuclein may lead to the sequestration and, therefore, cellular depletion of heat shock proteins, which makes the neurons more prone to degeneration, conclude the researchers. In an accompanying commentary, Dr Stephen Helfand from the University of Connecticut Health Center, US, says that the ability of heat shock proteins to protect against neurodegeneration may explain the diversity of insults that are associated with an increased risk of PD, as well as the puzzling protective effect of smoking. 2 He suggests that ‘risk factors may hamper the normal activity of chaperones, thus accelerating neurodegeneration, whereas the oxidative damage caused by smoking may induce a general stress response that increases production of chaperones and inadvertently protects neurons’. Dr Helfand notes that chaperone therapies are already in clinical trials for the treatment of tumours and, therefore, their therapeutic potential in patients with PD could be rapidly evaluated. 1. Auluck PK, et al. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295: 865-868, 1 Feb 2002. 2. Helfand Sl. Chaperones take flight. Science 295: 809-810, 1 Feb 2002. 800888098 1 Inpharma 23 Feb 2002 No. 1326 1173-8324/10/1326-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

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Transcript of Chaperone therapy: protective against Parkinson's disease?

Inpharma 1326 - 23 Feb 2002

Chaperone therapy: protectiveagainst Parkinson’s disease?

Augmentation of chaperone stress pathways may be anovel and effective way of ameliorating the toxicityassociated with α-synuclein that is observed inParkinson’s disease (PD) and several other humanneurodegenerative disorders, report researchers fromthe US.1

They evaluated the loss of dopaminergic neuronsassociated with the expression of α-synuclein inDrosophila models of PD. These models expressed wild-type human α-synuclein, or the two mutant formspathogenic for familial PD.

Hsp70 prevents neuronal lossExpression of either wild-type or mutant α-synuclein

in the Drosophila models led to a marked loss ofdopaminergic neurons in the dorsomedial cluster. Inaddition, impairing the activity of the endogenouschaperone Hsc4 in the Drosophila models led to a morerapid loss of neurons.

However, coexpression of a human chaperone, heatshock protein (Hsp)70, with α-synuclein completelyprevented the loss of dopaminergic neurons seen inDrosophila models expressing α-synuclein alone. Theresearchers comment that the protection was specific toHsp70 as coexpression of a control protein (β-galactosidase) did not prevent α-synuclein associatedneuronal loss.

Although human Hsp70 prevented the loss ofdopaminergic neurons in the Drosophila models, it didnot prevent the formation of protein inclusions that areanalogous to Lewy bodies and Lewy neurites, despitebeing present in the inclusions.

These data suggest that Hsp70 may be a critical part ofthe arsenal that prevents α-synuclein associated toxicity,or alternatively, the expression of α-synuclein may leadto the sequestration and, therefore, cellular depletion ofheat shock proteins, which makes the neurons moreprone to degeneration, conclude the researchers.

In an accompanying commentary, Dr StephenHelfand from the University of Connecticut HealthCenter, US, says that the ability of heat shock proteins toprotect against neurodegeneration may explain thediversity of insults that are associated with an increasedrisk of PD, as well as the puzzling protective effect ofsmoking.2 He suggests that ‘risk factors may hamper thenormal activity of chaperones, thus acceleratingneurodegeneration, whereas the oxidative damagecaused by smoking may induce a general stress responsethat increases production of chaperones andinadvertently protects neurons’.

Dr Helfand notes that chaperone therapies are alreadyin clinical trials for the treatment of tumours and,therefore, their therapeutic potential in patients with PDcould be rapidly evaluated.1. Auluck PK, et al. Chaperone suppression of alpha-synuclein toxicity in a

Drosophila model for Parkinson’s disease. Science 295: 865-868, 1 Feb 2002.2. Helfand Sl. Chaperones take flight. Science 295: 809-810, 1 Feb 2002.

800888098