Post by Lincoln Tracy
What's the science?
Parkinson’s disease (PD) is a chronic progressive neurological disorder and the most common age-related movement disorder characterised by a wide spectrum of motor and non-motor features. Classic motor symptoms include shaking, rigidity, and difficulty with walking. Moreover, sleep disturbances, anxiety, depression, cognitive decline, and dementia are also common among PD patients. The motor symptoms arise through the death of dopamine neurons in an area of the brain called the substantia nigra. The key neuropathological feature of PD are Lewy bodies and Lewy neurites, which contain a protein called alpha-synuclein (αSyn). Lewy bodies accumulate in various regions of the brain in PD, including the substantia nigra. However, the process by which the Lewy bodies accumulate, and the details of their structure is unknown. This week in Nature Neuroscience, Shahmoradian and colleagues present a 3D view of the internal structure of Lewy body pathologies through the use of various advanced light and electron microscopy techniques.
How did they do it?
First, the authors collected postmortem brain tissue samples from five donors who had a clinical diagnosis of PD from the Netherlands Brain Bank. Second, they used correlative light and electron microscopy —a combination of light microscopy and electron microscopy—to identify the Lewy body pathology in the brain tissue samples and examine their ultrastructure. They also used serial block-face scanning electron microscopy (SBFSEM) and transmission electron microscopy (TEM) to visualize the shape and structure of the Lewy bodies on a nanometer scale. Finally, they used stimulated emission depletion (STED) microscopy in a second set of brain tissue samples from 14 donors with PD who had coherent anti-Stokes Raman spectroscopy (CARS), and lipidomics to corroborate the light and electron microscopy, SBFSEM, and TEM findings.
What did they find?
Using the correlative light and electron microscopy approach, the authors captured a 3D structure of 17 Lewy bodies and Lewy neurites (LNs) that contained αSyn. The majority of the αSyn inclusions consist mainly of membrane fragments, intact-looking and distorted mitochondria and other organelles, but have in most cases none or negligible quantities of protein fibrils. The findings confirm that the protein αSyn is a major constituent of Lewy bodies, but that they have a high degree of compositional heterogeneity and complexity.
Further, these findings support the hypothesis that potentially damaged organelles and impaired organeller trafficking play a key role in the formation of Lewy bodies. Next, the SBFSEM data showed the Lewy body pathology contained aggregated intracellular material, including crowded mitochondria, lysosomes and other organelles, and a shell of mitochondria surrounding some of the inclusions. The TEM images displayed the ultrastructure of the Lewy body pathology more clearly and revealed the pathologies contained membrane fragments and lipids. The independent techniques of STED microscopy, compositional mapping methods (CARS), and mass spectrometry confirmed the microscopy findings that Lewy bodies and Lewy neurites contain αSyn, lipids, lysosomes, and mitochondria.
What's the impact?
These findings further our understanding of Lewy body pathology within the human brain while providing support for the hypothesis that impaired organelle trafficking is a key driver of disease progression in PD. Further studies are needed to examine the structure of Lewy body pathology across different stages of PD. Improving the understanding of how PD develops could trigger further studies on Lewy pathology, including mechanistic ones, that will assist in identifying better biomarkers and urgently needed new treatments for the disease.
Shahmoradian et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nature Neuroscience (2019). Access the original scientific publication here.