Insights into Lewy body disease from rare neurometabolic disorders

Abstract

Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers-Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of α-synuclein. In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated α-synuclein may generate insights into predisposing factors for α-synuclein aggregation in idiopathic Lewy body diseases.

Keywords: Alpha-synuclein; Cholesterol; Iron; Lewy body; Mitochondria; Sphingolipids.

Fig. 1

In contrast to control cerebellum, which shows a clear layer of Purkinje cells (arrows) on H&E stain (A.i.), individuals with POLG mutations typically show a loss of Purkinje cells, with some dystrophic remnants of Purkinje cells (arrow), alongside associated Bergmann gliosis (arrowheads; A.ii.). The substantia nigra of a 59 year old male with a POLG mutation shows α-synuclein-immunoreactive Lewy bodies (arrowheads; B.i.), as does the temporal cortex of a 79 year old male with a POLG mutation (arrowheads; B.ii.). Krabbe disease patients show clusters of lipid-filled multi-nucleated globoid cells (arrowheads) and single mononucleated foamy macrophages (arrows) in the medial lemniscus of a 10 month old male (C.i.) and occipital white matter of a 9 month old male (C.ii.). α-Synuclein immunohistochemistry of Krabbe disease cases demonstrates spherical inclusions in frontal cortex of a 10 month old male (D.i.) and the putamen of a 12 month old female (D.ii.). Scale bars = 200 µm (A.i., B.i., B.ii.), 100 µm (A.ii., C.i., C.ii., D.i.), 50 µm (D.ii.)