Mitochondrial ultrastructural abnormalities and disrupted neurotransmitter-storage bodies in Parkinson’s disease

Ismini Kloukina1, Virginia Kriho2, Sophia Havaki1,3 Marietta R. Issidorides 4 

1 Neurobiology Research Institute, Theodor Theohari Cozzika Foundation, Athens, Greece

2 Dept. of Anatomy & Cell Biology, College of Medicine, University of Illinois at Chicago, USA

3 Lab of Histology and Embryology, Medical School, University of Athens, Greece

4 Dept. of Psychiatry, University of Athens, Medical School, Eginition Hospital, Greece

Our previous studies demonstrated that Lewy Bodies (LB) emanate from cytoplasmic spherical inclusions - termed protein bodies (pb) - which are normal components of human monoamine neurons. In Parkinson’s Disease (PD), pb are reduced or missing, while two of their major constituents –basic proteins and sphingomyelin- are detected in the LB. Ultrastructurally, in control brains, pb originate as “dense bodies” inside mitochondria, which gradually lose their cristae and invest the mature pb with their double membrane; pb are storage sites of neurotransmitters (Issidorides et al., 2004). Since, several investigators have confirmed in PD the involvement of mitochondrial dysfunction, we investigated the ultrastructure of mitochondria to elucidate their contribution to PD pathogenesis.

We studied fresh frozen post-mortem tissue of substantia nigra and locus coeruleus of 9 PD patients and 5 controls. The potassium permanganate (KMnO4) method, suitable for membrane preservation and forming electron-dense precipitates with catecholamines, was applied. 

In control neurons, normal mitochondria and mature pb with electron-dense core were observed. In PD neurons, few mature pb were evident. Disrupted pb with split outer membranes and reduced electron-density of the core, indicating deficiency of the neurotransmitter were observed. Swollen mitochondria with missing cristae or with inner membranes forming stacks or concentric structures were evident. Most striking was budding of the mitochondrial outer membrane and expansion of the intermembrane space. Formation of mature pb was absent.

These results signify that the contribution of abnormal mitochondria to PD is a consequence of their normal role in giving rise to neurotransmitter-storage bodies, which was found to be abrogated, resulting in lack of pb and, thus, in lack of storage sites for the neurotransmitter. Defective sequestration of the neurotransmitter into these pb vesicles would accumulate free dopamine in the cytoplasm, generating reactive oxygen species, a key event in the demise of dopaminergic neurons in PD.