Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

Abstract

Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Keywords: Alpha-synuclein; Autophagy; Catabolism; Lewy body; Lipid metabolism; Mitochondria.

Fig. 1

α-Synuclein immunoreactivity in rare monogenic disorders in comparison to idiopathic LB diseases. α-Synuclein-positive punctae and small, LB-like structures, in temporal cortex grey-white matter junction in a 10 month old boy with Krabbe disease (a and a.i.) in comparison to superficial pyramidal layer of temporal cortex in a 91-year-old female with dementia with LBs (b–b.i.). LBs in substantia nigra (c) and nucleus basalis of Meynert (d) of a 87-year-old female with dementia with LBs in comparison to the substantia nigra (e) and nucleus basalis of Meynert (f) of a 79-year-old male with a POLG mutation and longstanding progressive external opthalmoplegia taken from our previous report of LB pathology in mitochondrial disease [28]. Antibodies used were BD Transductions Clone 42 (1:1,000; a–b.i.) and Novocastra KM51 (1:250; c–f). Scale bars = 100 µm (a and b), 50 µm (c and e) and 200 µm (d and f)

Fig. 2

ShinyGO [38] analysis demonstrated three broad clusters into which enriched biological processes clustered: lipid metabolism, catabolic processes, and mitochondrial homeostasis and autophagy

Fig. 3

LB dementia is associated with changes to the mitochondrial respiratory chain. Representative images from our previous study in the nucleus basalis of Meynert [50] demonstrating respiratory chain subunit expression in control (A.i.–A.iv.), incidental LB disease (iLBD) (B.i.–B.iv.) and LB dementia (LBD) (C.i.–C.iv.) cases, highlighting reductions in Complex I in LBD compared to iLBD and control. As detailed in [50], sections were stained with ChAT (Sigma HPA048547, 1:100), NDUFB8 (Abcam ab110242, 1:100), COX4 (Abcam ab110261, 1:100) and VDAC1/porin (Abcam ab14734, 1:200). Scale bars = 10 µm. Dot plots show group level z scores of Complex I NDUFB8 and IV/COXIV integrated densities normalised to porin integrated density, as explained in detail in [50], from approximately 50 neurons per case (control N = 8, LBD N = 8, iLBD N = 2). Bars are means and standard deviation. *p < 0.05. Originally published in [50] by BioMed Central and provided here under a Creative Commons Attribution Licence 4.0

Fig. 4

Multiple pathways leading to Lewy body formation. a Mutations causing mitochondrial dysfunction may contribute to Lewy body formation by increasing oxidation of α-synuclein, leading to aggregation and eventual formation of a Lewy body. b Mutations in genes encoding lipid-degrading enzymes such as GALC, GBA and CATD can directly lead to increased levels of lipid substrates known to be permissive to α-synuclein aggregation, including psychosine, glucosylsphingosine and heparan sulphate, respectively. Alternatively, mitochondrial dysfunction (a) leads to increased abundance of lipid droplets known to facilitate α-synuclein aggregation. Elevated levels of lipids are likely to overwhelm autophagic mechanisms within neurons, leading to autophagy failure after sustained elevations in lipid species (c). c Autophagy failure induces mitochondrial dysfunction (a) by impeding mitochondrial quality control by reductions in mitophagy, and potentially also leads to α-synuclein aggregation by reduced turnover (dashes). (d) Accumulation of α-synuclein may occur directly due to disassembley of tetramers into aggregation-prone monomers or increased abundance of α-synuclein protein, or indirectly through (a), (b), or (c). Increased accumulation of α-synuclein over time leads to assembly into Lewy bodies. Black lines indicate the mechanism directly affected by specific mutations, blue lines indicate indirect influences on α-synuclein aggregation through interactions between mechanisms, and red lines indicate direct influences on α-synuclein aggregation