Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

in Current Neurology and Neuroscience Reports (2022), 22(8), 427440

Purpose of Review: Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to ... [more ▼]

Purpose of Review: Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. Recent Findings: Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. Summary: In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD. © 2022, The Author(s). [less ▲]

Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function.

in Cell death and differentiation (2012), 19(2), 257-66

The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that ... [more ▼]

The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress. [less ▲]