Neurology Practice Changers 2014

Bret S. Stetka, MD; Andrew N. Wilner, MD


December 08, 2014

In This Article

Do Migrating, Pathologic Proteins Cause Neurodegeneration?

Numerous mechanisms have been proposed over the years to explain neurodegenerative disorders. But a relatively new theory gaining fast momentum is the prion hypothesis—the idea that such conditions as Parkinson disease (PD), Alzheimer disease (AD), and Huntington disease (HD) are caused by, or at least involve, the propagation of misfolded proteins throughout the brain.

Past work has shown that the injection of alpha-synuclein—the protein that forms the characteristic Lewy bodies in PD—is internalized by neurons in both in vitro and in vivo models.[14,15,16] Even more compelling is work showing that intracerebral injection of alpha-synuclein results in its accumulation in neurons, as well as the migration of synuclein pathology to neighboring brain regions.[17]

The authors of a study[18] published earlier this year in the Annals of Neurology injected Lewy body extracts from the substantia nigra of patients with PD into the nigra or striatum of mice and macaque monkeys. Alpha-synuclein was found to accumulate in the host neurons concurrently with neurodegeneration at dopaminergic nerve terminals that, at 4 to 17 months out, mimicked PD pathology.

Later this year, a group of international, interdisciplinary investigators published work in Neurobiology of Disease[19] proposing a mechanism for how alpha-synuclein spreads from neuron to neuron in PD. The group used an antibody that distinguishes between normal and abnormal forms of alpha-synuclein to determine that human neurons transfer pathologic forms of the protein to neighboring cells. A related study by the same group successfully used the antibody to detect abnormal synuclein in the cerebrospinal fluid, an approach that could one day help diagnose PD and other synucleopathies early in the disease course.

Research[20] published in Nature Neuroscience in August reported similar findings for the huntingtin protein in HD, whereas misfolded, prion-like tau protein may be involved in AD pathogenesis.[21]

This unifying theory that migrating proteins are responsible for a diverse group of neurodegenerative diseases, such as PD, HD, and AD, departs dramatically from conventional wisdom. If this proposed pathophysiologic mechanism turns out to be correct, it would provide opportunities for early diagnosis and the development of unique therapies to attack and disable pathologic proteins.


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