Parkinson's disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

Abstract

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson's disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

Keywords: Lewy body; Parkinson’s disease; X-ray diffraction; cross-β structure.

Fig. 1.

Microbeam XRD analysis of mouse SPs showing a sharp diffraction peak corresponding to d = 0.47 nm. (A) “Top” image. (B) “Bottom” image. (C) Difference image obtained by subtracting B from A. (D) A 2D map of total wide-angle scattering intensity. A 40 × 40 scan was performed with 5-µm steps. (E) Optical micrograph of a Congo-Red–stained brain slice. Because the optical axis of the microscope was not perfectly coaxial with the X-ray beam, the areas in D and E are slightly misaligned. (Scale bar, 50 µm.) (F) Circularly averaged X-ray scattering intensity profile of C.

Fig. 2.

Analysis of human LBs showing a sharp diffraction peak corresponding to d = 0.47 nm (sample from patient 1 [Pt. 1]). (A) Top image. (B) Bottom image. (C) Difference image obtained by subtracting B from A. (D) A 2D map of total wide-angle scattering intensity. A 20 × 20 scan was performed with 3-µm steps. (E) Micrograph of an antibody-stained brain section. (Scale bar, 10 µm.) (F) Circularly averaged X-ray scattering intensity profile of C.

Fig. 3.

Analysis of human LBs showing a broad peak around d = 0.47 nm. (A) Top image (sample from Pt. 1). (B) Bottom image. (C) Difference image obtained by subtracting B from A. (D) A 2D map of total wide-angle scattering intensity. A 20 × 20 scan was performed with 3-µm steps. (E) Micrograph of an antibody-stained brain section. (Scale bar, 10 µm.) (F) Circularly averaged X-ray scattering intensity profile of C.

Fig. 4.

Analysis of human LBs not showing a peak corresponding to d = 0.47 nm (sample from Pt. 2). (A) Top image. (B) Bottom image. (C) Difference image obtained by subtracting B from A. (D) A 2D map of total wide-angle scattering intensity. A 20 × 20 scan was performed with 5-µm steps. (E) Micrograph of an antibody-stained brain section. (Scale bar, 10 µm.) (F) Circularly averaged X-ray scattering intensity profile of C.