Parkinson Disease: Cuervo AM

Morimoto RI, Cuervo AM. · Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #19228787 No free full text.

Abstract: All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. Alterations in these fine-tuned mechanisms underlie the pathogenesis of severe human diseases including, among others, common neurodegenerative disorders such as Alzheimer's or Parkinson's disease. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age, even in the absence of disease, and it likely contributes to different aspects of "normal" aging. A group of experts in different aspects of the biology of aging met recently to discuss the implications of altered protein homeostasis in aging, the current gaps in our understanding of the mechanisms responsible for proteome maintenance, and future opportunities for discovery in this area. We summarize here some of the key topics and main outcomes of the discussions.

Ventruti A, Cuervo AM. · Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. · Curr Neurol Neurosci Rep. · Pubmed #17764636 No free full text.

Abstract: All cellular components are subjected to continuous surveillance by intracellular quality control systems. The major players involved in this quality control are molecular chaperones, which detect the abnormal components, and proteases, which eliminate them from the cell. Malfunctioning of the cellular surveillance systems inexorably leads to cell toxicity, and often cell death, due to the accumulation of unwanted nonfunctional components inside cells. In this work, we review the contribution of the autophagic system to cellular quality control and the consequences that autophagy malfunction has on cellular function. Special emphasis is made on the recently identified role of this system in maintenance of neuronal homeostasis and in the links currently established between alterations in the autophagic system and major neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Bandyopadhyay U, Bandhyopadhyay U, Cuervo AM. · Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. · Exp Gerontol. · Pubmed #16860504 No free full text.

Abstract: Different conditions, ranging from genetic mutation to post-translational modification, result in the intracellular presence of misfolded or conformationally altered proteins. These abnormal proteins tend to organize in toxic oligomeric structures often resulting in cellular death. Alterations in the function of the surveillance systems that normally repair or remove abnormal proteins are the basis of many neurodegenerative disorders. In this review, we focus on such protein conformational disorders and on the role that altered function of intracellular proteolytic systems, in particular autophagy, plays in the evolution of these diseases. Using Parkinson disease as a main example, we recapitulate the different stages of this protein conformational disorder at the cellular level and relate them with changes in the different types of autophagy. Finally, we also comment on the effect that aggravating conditions, such as oxidative stress and aging, have on the functioning of the autophagic system and its ability to cope with altered proteins.

Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM. · Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA. · J Clin Invest. · Pubmed #18172548 links to  free full text

Abstract: Altered degradation of alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that alpha-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of alpha-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic alpha-syn mutations are rare, alpha-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of alpha-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified alpha-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.