Is Parkinson's disease a prion disorder?

In this issue of PNAS, Desplats et al. (1) demonstrate that nerve cells that overexpress tagged α-synuclein can transmit the protein to neural stem cells in both in vitro and in vivo models. This important study could explain the remarkable finding that human embryonic dopamine nerve cells implanted into the striatum of patients with Parkinson's disease (PD) develop PD pathology with loss of dopamine markers and classic Lewy bodies (2, 3). It also provides insight into how α-synuclein pathology might sequentially spread throughout the nervous system in PD. PD is an age-related, neurodegenerative disease that affects approximately one million persons in the United States. Pathologically, the disease is characterized by a loss of dopamine neurons in the substantia nigra pars compacta coupled with proteinaceous inclusions in nerve cells and terminals, known as Lewy bodies and Lewy neurites, respectively. PD pathology is also known to affect nondopamine neurons in the upper and lower brainstem, olfactory system, cerebral hemisphere, spinal cord, and autonomic nervous system. The cause of cell death in PD is not known, but proteolytic stress with the accumulation of misfolded proteins has been implicated (4). That the aberrant accumulation of proteins might feature in the pathogenesis of PD is a reasonable posit, given that Lewy bodies, the hallmark of the disease, are composed of a variety of aggregated proteins. Among these, α-synuclein has attracted particular attention. α-Synuclein is a 140-aa synaptic protein that is unstructured in aqueous buffers, but adopts an α-helical-rich conformation when bound to membranes (5), and can acquire a β-sheet-rich structure that readily polymerizes into fibrils when present in high concentration or in a mutant form (6). …