Progress and Prospects in Parkinson's Research/Pathogenesis/Current Parkinson's Paradigm

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Recent progress in Parkinson's research has led to the evolution of a new paradigm.

There are various facets to the new model whose features include the role of alpha-synuclein oligomers, mitochondrial disruption, dysfunction of the waste-disposal systems of cells (UPS and autophagy), inflammation and the production of reactive oxygen species (ROS), the interaction of environmental and genetic factors, the spread of the disease from the peripheral to the central nervous system and the relative vulnerability of certain types of neuron. A review in Nature Medicine in 2010 addresses this paradigm.

Crucial to the paradigm shifts that have occurred has been the application of powerful and sophisticated biochemical, pathological, neuroimaging, genetic, anatomic, pharmacologic and neurologic techniques, amongst others.

While it has been been necessary to work at the level of intricate and subtle detail, the Systems Biology approach has provided a top-down view which promises to integrate the progress made in various fields and disciplines and provide a holistic view of the mechanism and processes intrinsic to this disease and raise insights into what might be crucial targets for therapeutic intervention.

There has been much reliance on in vitro investigations and animal models whose relevance to the human condition must always be subject to cautious appraisal.

Features of the Current Parkinson's Paradigm
These features could provide the framework for organising the topics on the Progress and Prospects in Parkinson's Research page

The pathogenic state in Parkinson's and other neurological diseases is complex and involves the disruption of a number of interconnected mechanisms and biochemical pathways. It is worth asking what the normal state of these is for an individual without Parkinson's.

Homeostasis
In an individual without Parkinson's presumably the following situation of homeostasis obtains:
 * Alpha-synuclein molecules are largely in their native state and the few which are misfolded or are oligomerising in a potentially harmful way are detected and removed by the normal garbage collection services of the cell notably the Ubiquitin Proteasome System (UPS) and by autophagy. Chaperone proteins such as the heat shock proteins are also produced to promote and maintain the native configuration.
 * The existence of oxidative and nitrative stress resulting from the production of free radicals, Reactive Oxygen Species and free iron is kept within acceptable limits by a complex variety of mechanisms and biological agents.
 * Inflammation is kept to acceptable levels through the operation of the innate and adaptive immune systems.
 * Damaged and dysfunctional mitochondria are removed and repaired by the normal mitophagy, fission and fusion mitochondrial processes.
 * Many other complex processes cause particular proteins and enzymes to be expressed to maintain homeostasis
 * Add more
 * Note that ageing affects the ability to maintain homeostasis.
 * for all the above.

(Go on to say that perturbations can occur through infection and trauma to disrupt homeostasis and to test the limits of the homeostatic mechanisms. A persistent state where damaging mechanisms are out of control or barely controlled can set in.  Describe the self-perpetuating cycle.  Inadequacies in the homeostatic mechanisms, maybe due to genetic variations, may mean that a disease state occurs more easily than normal.  Give examples e.g. DJ-1, SNCA, Parkin)

Recent significant research
The association of alpha-synuclein with Parkinson's pathology is currently being extensively studied and a hypothesis gaining currency is that some oligomeric forms of the protein are toxic. A recent paper backs this up. Cremades et al report observing that non-toxic oligomers can convert to stable toxic oligomers which themselves can aggregate further to form fibrils. Moreover the fibrils can disaggregate into the toxic oligomers. The oligomers are toxic because they promote the formation of reactive oxygen species (ROS). There are a number of implications from these observations and it would be good to have these explored in the alpha-synuclein sub-page that remains to be written. Droflet (talk) 17:04, 11 July 2012 (UTC)

See 3 hits in understanding_pathogenesis in the Magazine section. See also the Discussion page.