Novas pistas sobre as bases moleculares do cancro e doença de Parkinson

Um grupo de cientistas do Instituto de Medicina Molecular (IMM), liderado por Tiago Outeiro, e investigadores na Alemanha e no Reino Unido, estudaram um gene associado à doença de Parkinson e a forma como atua, abrindo portas ao desenvolvimento de novas estratégias terapêuticas contra esta doença, mas também contra o cancro. O trabalho de investigação vem mostrar que a doença de Parkinson pode ter uma causa genética - até recentemente os indícios apontavam para causas ambientais - trazendo nova esperança para o seu tratamento. O grupo estudou um dos genes associados à doença de Parkinson, o gene que codifica a proteína DJ-1. Este gene está associado também ao cancro, porque a função da proteína pensa-se que está relacionada com a defesa contra stress oxidativo. Ou seja, uma vez identificada a função do gene defeituoso, deverá ser mais fácil identificar «onde é que as coisas correram mal», sendo DJ-1 um exemplo particularmente interessante, porque é um gene que causa várias formas de Parkinson, mas também está ligado ao cancro, ao Alzheimer e a outras doenças neurodegenerativas, o que sugere que desempenha um papel importante na protecção contra os efeitos do envelhecimento.

Autores e Afiliações:

Leonor Miller-Fleming,^a,^b, Pedro Antas,^a, Teresa Faria Pais,^a, Joshua L. Smalley,^b,c, Flaviano Giorgini,^b,1,

and Tiago Fleming Outeiro,^a,d,e,1

a. Instituto de Medicina Molecular, 1649-028 Lisbon, Portugal;

b. Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;

c. Systems Toxicology Group, Medical Research Council Toxicology Unit, University of Leicester, LE1 9HN Leicester, United Kingdom;

d. Instituto de Fisiologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal;

e. Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, 37073 Göttingen, Germany

Abstract:

Based on great similarities with mammalian cells, yeast cells have been often used as ideal model organisms to study complex basic processes. Apart from an even diploid set of chromosomes, yeast cells harbor numerous proteins similar to human cells that make them in particular suitable for the biotechnological development of active components. To understand the function of DJ-1 proteins for the development of the neurodegenerative diseases Morbus Parkinson, the scientists focused on the homologues members of the Hsp31 family (Hsp31, Hsp32, Hsp33, Hsp34) in yeast cells, which belong to the highly conserved DJ-1 superfamily. „At the cellular level, the central role of proteins of the DJ-1 superfamily so far is not well understood. We did not know, which processes exactly are impaired by mutation and lead to altered protein function that in consequence cause this disease“, Prof. Tiago F. Outeiro and Dr. Flaviano Giorgini, the leading authors of the study, explain. For the first time, they discovered that the proteins are important for maintenance of the normal life span of yeast cells. Under conditions of stress, e.g. when glucose levels are limited, the cell has to drive a reprogramming to switch to other cellular components that serve as energy sources. The recently published study demonstrates that this essential reprogramming in yeast cells, also known as diauxic shift, essentially requires the presence of Hsp31 proteins. Inversely, deletion of the genes that produce Hsp31 proteins impairs the reprogramming of yeast cells, and reduces normal cellular lifespan. Moreover, the scientists discovered the participation of Hsp31 proteins in the regulation of autophagy – a process that the cells employ to breakdown and recycle damaged cellular components, which guarantees cell regeneration and the maintenance of healthy cells. Interestingly, both diauxic shift and autophagy have been found to be impaired in Parkinson’s Disease and cancer. Yeast and mammalian cells often contain highly conserved homologues proteins, therefore many cellular processes are executed in a quite similar manner.

Revista:

Proceedings of the National Academy of Sciences of the United States of America

Link:

http://www.pnas.org/content/early/2014/04/01/1319221111.long