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

Accumulation of the protein alpha-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). alpha-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 alpha-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Automated summary

The accumulation of alpha-synuclein into insoluble intracellular deposits called Lewy bodies is the characteristic neuropathological feature of LB diseases such as Parkinson's disease. Genetic analyses and studies on model systems suggest that alpha-synuclein aggregation is a critical pathogenic event in LB diseases. Disorders not traditionally characterized as synucleinopathies may also be disproportionately vulnerable to LB formation, possibly due to disturbances in processes related to lipid homeostasis, autophagy, and mitochondrial function. These findings highlight the potential influence of impairments in these processes in the etiology of LB formation.