Formation and significance of intracytoplasmic neuronal inclusions in Parkinson’s Disease

Formation and significance of intracytoplasmic neuronal inclusions in Parkinson’s Disease

From a neuropathological point of view, Parkinson’s disease (PD) is characterized not only by the loss of nigrostriatal dopaminergic neurons but also by the presence, in every affected brain region, of intraneuronal proteinacious cytoplasmic inclusions, called Lewy bodies (LBs). LBs classically appear in pigmented nigral neurons with hematoxylin/eosin staining as one or more eosinophilic spherical body with a dense core surrounded by a halo. LBs contain a variety of proteins, of which alpha-synuclein, a mutation in which gene was the first to be identified in a familial form of PD, is a major component.

Although LBs were first described by Friedrich Lewy in 1912, their complex ultrastructure and composition has remained unknown until relatively recently and their machanisms of formation and significance to the disease process is still a mystery. The presence of Lewy bodies in PD suggests that defective protein handling may contribute to the pathogenesis of the disease. In this context, we have shown that defective lysosomal-mediated degradation contributes to intracytoplasmic inclusion formation and cell death in experimental in vitro and in vivo models of PD, as well as in PD patients. More importantly, pharmacological or genetic restoration of lysosomal function in affected cells is able to attenuate inclusion formation and neuron cell death in these experimental PD models. In addition, we have shown that increased levels and post-translational modifications of alpha-synuclein play an instrumental role in PD-linked dopaminergic neurodegeneration in vivo.



Autophagy defects in experimentalParkinson’s disease. Inhibition of complex I with MPP+ impedes the flow of electrons along the mitochondrial electron transport chain, resulting in an increased production of reactive oxygen species (ROS). Mitochondria derived ROS damage various cellular elements, including the inner mitochondrial lipid cardiolipin, the oxidation of which disrupts the binding of cytochrome c (Cyt c) to the inner mitochondrial membrane, thereby increasing the ‘releasable’ soluble pool of cytochrome c into the mitochondrial intermembrane space (IMS) that can be subsequently released to the cytosol by the pro-apoptotic protein Bax. Once in the cytosol, cytochrome c actives downstream executioner caspases, leading to cell death. Enhanced mitochondria-derived ROS have also been shown to induce the abnormal permeabilization of lysosomal membranes and subsequent disruption of lysosomal structural integrity. Lysosomal breakdown results in a defective clearance and subsequent accumulation of altered mitochondria and undegraded autophagosomes (APs). The accumulation of dysfunctional mitochondria can contribute to cell death by an increased release of mitochondrial apoptogenic factors from damaged mitochondria. Furthermore, the undegraded autophagosomes may start to fill large portions of the neuron cell body and interfere with cellular functions, and they may eventually form Lewy bodies. Furthermore, lysosomal membrane permeabilization results in the leakage of lysosomal proteases into the cytosol, some of which, such as cathepsin B (CB) and CD, can remain active at neutral pH and cause the digestion of vital proteins or the activation of additional hydrolases, including caspases. All of these pathogenic events, including apoptotic cell death, can be attenuated by rapamycin treatment. In particular, in addition to its role in inducing autophagosome formation, rapamycin was shown to restore impaired lysosome-mediated autophagosome clearance in MPTP-treated mice by boosting lysosomal biogenesis and promoting autophagolysosome formation, all of which resulted in an attenuation of dopaminergic cell death in these animals. From Bové et al.,Nature Reviews Neuroscience (2011).


Additional reading:

Loss of ATP13A2/PARK9 induces general lysosomal deficiency: implications for Parkinson’s disease.
Dehay B., Ramirez A., Martinez-Vicente M., Perier C., Canron M.H., Doudnikoff E., Vital A., Vila M., Klein C. and Bezard E.
Proceedings of the National Academy of Sciences USA [in press] (2012)

Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease.
Sánchez-Danés A., Richaud-Patin Y., Carballo-Carbajal I., Jiménez-Delgado S., Gaig C., Mora S., Di Guglielmo C., Ezquerra M., Patel B., Giralt A., Canals J.M., Memo M., Alberch J., López-Barneo J., Vila M., Cuervo A.M., Tolosa E., Consiglio A. and Raya A.
EMBO Molecular Medicine [Epub ahead of print] (2012)

Fighting neurodegeneration with rapamycin: mechanistic insights.
Bové J., Martínez-Vicente and Vila M.
Nature Reviews Neuroscience 12(8):437-52 (2011)

Lysosomal membrane permeabilization in Parkinson’s Disease.
Vila M., Bové J., Dehay B., Rodríguez-Muela N. and Boya P.
Autophagy 7(1):98-100 (2011)

Pathogenic lysosomal depletion in Parkinson’s Disease.
Dehay B., Bové J., Rodríguez-Muela N., Perier C., Recasens A., Boya P. and Vila M. Journal of Neuroscience 30(37):12535-12544 (2010)

Selective noradrenergic vulnerability in alpha-synuclein transgenic mice.
Sotiriou E., Vassilatis D.K., Vila M. and Stefanis L.
Neurobiology of Aging 31(12):2103-14 (2010)

Resistance of a-synuclein null mice to the parkinsonian neurotoxin MPTP.
Dauer W., Kholodilov N., Vila M., Trillat A.C., Goodchild R., Larsen K., Staal R., Tieu K., Schmitz Y., Yuan C.A., Jackson-Lewis V., Hersch S., Sulzer D., Przedborski S., Burke R. and Hen R.
Proceedings of the National Academy of Sciences USA, 99:14524-14529 (2002)

Alpha-Synuclein upregulation in substantia nigra dopaminergic neurons following the administration of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Vila M., Vukosavic S., Jackson-Lewis V., Jakowec M. and Przedborski S.
Journal of Neurochemistry, 74:721-729 (2000)