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

Daniel Erskine,David Koss,Johannes Attems,Viktor I Korolchuk,Ian Mckeith,Tiago F Outeiro

doi:10.1007/s00401-021-02266-7

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.

Highlights

The Lewy body (LB) diseases, including Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (LBs) (DLB), are thought to lie on a clinical and pathological continuum of motor and cognitive symptoms [60].PD presents with a rest tremor, bradykinesia and an unsteady gait, that can develop into dementia termed PDD, whilst dementia with LBs (DLB) presents with cognitive impairment that can later develop into motor symptoms similar to PD [75]
Evaluation of the genes associated with LB pathology using ShinyGo largely confirmed the findings from PANTHER, with enriched biological processes functionally clustered around two sub-groups of mitochondrial function/autophagy, and lipid metabolism, linked by catabolism (Fig. 2)
One of the primary reasons for the ascendency of α-synuclein in LB disease is that it is responsible for mutations causing the first identified form of familial PD and is a component of LBs [88]; a recent study has reported that the core of LBs may be composed of lipids and surrounded by dystrophic mitochondria [109]

Summary

Introduction

The Lewy body (LB) diseases, including Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LBs (DLB), are thought to lie on a clinical and pathological continuum of motor and cognitive symptoms [60].PD presents with a rest tremor, bradykinesia and an unsteady gait, that can develop into dementia termed PDD, whilst DLB presents with cognitive impairment that can later develop into motor symptoms similar to PD [75]. LBs are typically thought to be the hallmark pathological lesion associated with LB diseases, they are observed in cases of several rare genetic disorders, including some forms of familial PD [8], neurodegeneration with brain iron accumulation (NBIA) [104], lysosomal storage disorders [108] and mitochondrial diseases [28].

Results

Conclusion