The cell biology of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non–cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non–cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.

Metabolic alterations in a Drosophila model of Parkinson’s disease based on DJ-1 deficiency

“…PD is an incurable and complex disease in which mechanisms causing DA neuronal death are not clear yet [2,5]. Some authors have described a link between redox imbalance, energy failure and metabolic disturbances in PD, leading to the idea that it might be considered a metabolic disease [7,8].…”

“…DA neuron loss is accompanied, in some cases, by the presence of α-synuclein aggregates in the surviving neurons, known as Lewy bodies [2,4]. The exact mechanism behind DA neurodegeneration in PD is still unclear, being probably a combination of genetic predisposition and environmental factors [2,5]. Indeed, multiple pathways and mechanisms seem to participate in PD pathogenesis like accumulation of misfolded protein aggregates, mitochondrial dysfunction, increased oxidative stress (OS), energy failure, neuroinflammation, and genetic mutations [6].…”

“…Most PD cases are idiopathic (iPD), whose aetiology is multifactorial. However, 5-10% of PD patients suffer from monogenic forms of the disease caused by highly penetrant mutations that are family-linked [2,5]. In the last years, mutations in several genes have been associated with these familial forms of PD (fPD), allowing to discover different mechanisms underlying PD pathogenesis [5,9].…”

“…However, 5-10% of PD patients suffer from monogenic forms of the disease caused by highly penetrant mutations that are family-linked [2,5]. In the last years, mutations in several genes have been associated with these familial forms of PD (fPD), allowing to discover different mechanisms underlying PD pathogenesis [5,9]. Indeed, some of the proteins encoded by these genes are involved in a set of molecular pathways that upon perturbation trigger a neuropathology that resembles to, or is clinically indistinguishable from iPD, except for the age at onset [10].…”

Lipid droplets in the nervous system

“…Parkinson’s disease, the second most common neurodegenerative disease, involves motor symptoms such as tremors, rigidity, and bradykinesia and non-motor symptoms such as sleep disturbances and cognitive impairment ( Poewe et al, 2017 ). It is predominantly characterized by the loss of dopaminergic neurons in the substantia nigra and intracellular aggregation of α-synuclein protein ( Poewe et al, 2017 ; Panicker et al, 2021 ). Disturbances in lipid homeostasis have recently emerged as a common theme in Parkinson’s disease.…”