More than a Rumor Spreads in Parkinson's Disease

Abstract

As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies and Lewy neurites. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss. It is believed that the spreading of Lewy bodies through the nervous system is a consequence of the cell-to-cell propagation of αSyn, that can occur via sequential steps of secretion and uptake. Certain pathological forms of transmitted αSyn are able to seed endogenous counterparts in healthy recipient cells, thus promoting the self-sustained cycle of inclusion formation, amplification and spreading, that ultimately underlies disease progression. Here we review the cell-to-cell propagation of αSyn focusing on its role in the progression of Parkinson's disease.

Keywords: Lewy bodies; Parkinson's disease; alpha-Synuclein; cell-to-cell propagation; neurodegeneration; prion-like diseases.

Figure 1

Hypothetical model of α-Synuclein cell-to-cell transmission. In pathological conditions, αSyn is found as β-sheet-enriched amyloid aggregates and fibrils that reside within Lewy bodies and Lewy neurites (LBs/LNs). Neurons containing LBs (left) could release αSyn aggregates and seeds into the extracellular milieu by different mechanisms such as non-classical exocytosis or via exosomes (1). Extracellular αSyn is then internalized by endocytosis by neighbor neurons as well as glial cells (2). Due to its amyloidogenic nature, uptake of exogenous seeds promotes the structural corruption of endogenous counterpart in healthy recipient neuronal cells (right). Thus, monomers of the recipient cell are converted into aggregates and fibrils by direct action of exogenous seeds (3) and new LBs are formed (not shown). Neuronal viability is severely affected by two mechanisms; (i) the intrinsic cytotoxic properties of intracellular αSyn aggregates and (ii) indirectly by action of proinflammatory molecules released by glial cells activated upon exposure to extracellular αSyn seeds (4).