Parkinson Disease: Dauer W

Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J. · Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707, USA. · J Neurosci. · Pubmed #17978026 links to  free full text

Abstract: The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.

Dauer W, Przedborski S. · Department of Neurology, Columbia University, New York, NY 10032, USA. · Neuron. · Pubmed #12971891 No free full text.

Abstract: Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.

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.

Dauer W. · Departments of Neurology and Pharmacology, Columbia University, Neurological Institute of New York, Box 204, 710 West 168th Street, New York, NY 10032, USA. · Sci STKE. · Pubmed #17986711 No free full text.

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Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R. · Department of Neurology, Columbia University, New York, NY 10027, USA. · Proc Natl Acad Sci U S A. · Pubmed #12376616 links to  free full text

Abstract: Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of alpha-synuclein. Rarely, PD may be caused by missense mutations in alpha-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that alpha-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in alpha-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal alpha-synuclein function may be important to DA neuron viability.