Chapter Nine - Inflammation and Parkinson's disease pathogenesis: Mechanisms and therapeutic insight
Introduction
Selective vulnerability and distinct etiology characterize each neurodegenerative disorder. However in the last two decades, various common aspects have been identified as biological bases of these diseases. Protein misfolding, progressive widespread pathology, inflammation, mitochondrial dysfunction, anomalous glutamate receptor activation, a vascular component, and microbiota contributions are evident in virtually all neurodegenerative pathologies. The central pathogenetic role of oligomers, small soluble aggregates of misfolded protein, as principal neurotoxic element and pathology propagation vector led us to define the main neurodegenerative disorders as oligomeropathies.1 On the other hand, inflammation also is considered an inevitable component of the pathological scenario, not only when neurodegenerative processes are well established but, as recently shown, in the early phase of diseases.2 After Alzheimer's disease, Parkinson's disease (PD) is the most common neurodegenerative disorder. Selective neuronal vulnerability manifests as loss of dopaminergic neurons in the midbrain3 and the presence of Lewy bodies (LB), intracellular aggregates of α-synuclein (α-syn), in this region has been associated with neuronal dysfunction. Together with PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) collectively are referred to as synucleinopathies. These disorders are characterized by the presence of LB in neurons and glial cells. The clinical manifestations of PD include typical motor symptoms, bradykinesia, rigidity, and tremor, associated with nonmotor alterations such as cognitive impairment, mood disorders, dysautonomia, sleep alterations, and hallucinations. The pathogenetic role of α-syn has been investigated from different point of view and presence of α-syn in the enteric nervous system supports the etiological possibility of peripheral initiation of PD pathology. The formation of α-syn aggregates can be influenced by numerous factors, including posttranslational changes,4, 5 and the heterogeneity of the aggregates has been associated with different pathological phenotypes.6, 7 The role of the immune system and inflammation in PD pathogenesis is well established by experimental, genetic, neuropathological and clinical investigations.8, 9 The cross-talk between α-syn and the immune system has been proven at different levels.10, 11, 12, 13, 14 Furthermore, mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been associated with PD as well as immune-related disorders. LRRK2 also has been recognized as an immune system regulator.15 All these findings need to be translated into therapeutic strategies since numerous clinical trials based on the control of inflammation in PD have given unsatisfactory results. In this chapter, we present the state of the art in the field together with some results that we have obtained focused on α-syn aggregation and inflammation in a therapeutic perspective.
Section snippets
Parkinson's disease as an oligomeropathy
The presence of LBs is the main neuropathological hallmark of PD and LB dementia (LBD). These concentric hyaline cytoplasmic inclusions were originally described in the substantia innominata and the dorsal nucleus of the vagal nerve by Lewy in 1912.16, 17 They were named Lewy bodies in the 1980s and were found in the peripheral and central nervous system, and in other organs, of PD patients. A major breakthrough in the pathogenesis of PD occurred when mutations in the gene encoding α-syn (SNCA)
Role of inflammation
Inflammatory reaction has been observed in all neurodegenerative disorders, although distinct immune pathways can be identified for any single disease. In rare or diffuse neurodegenerative disorders, inflammatory activation has been studied and shows similarity and differences.1, 103 The immune process at the central level, defined as neuroinflammation, expressed different timing and pattern of activation compared to the peripheral reaction, although the factors involved are essentially the
Therapeutic approach: Possible role of doxycycline
Scientific research on the pathogenesis of neurodegenerative disorders, and in particular AD and PD, has grown almost exponentially in the 21st century. An incredible amount of data at many levels—epidemiological, genetic, pathogenetic, pharmacological—have been accumulated but it has been difficult to translate this knowledge into therapies. In PD, several symptomatic strategies have been available, with important positive results,178 However, we are still waiting for an approach that can slow
Conclusions
The central role played by α-syn oligomers and inflammation in the pathogenesis of PD and related synucleinopathies is well established. The recent findings at the experimental level and the investigations in human biological samples have substantially confirmed this view. In PD, the spreading of pathology is progressive and involves peripheral organs, thus it is reasonable to hypothesize that a seeding mechanism initiated by oligomers triggers a pathological process involving diffusion that
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2023, Journal of Psychiatric ResearchRepositioning doxycycline for treating synucleinopathies: Evidence from a pre-clinical mouse model
2023, Parkinsonism and Related DisordersCitation Excerpt :As shown in Fig. 4L, while the expression of BDNF was significantly lower in A53T + Veh compared to NTG + Veh mice, in A53T mice receiving Doxy, it was comparable to the level of NTG + Veh mice. Neurodegenerative disorders, such as PD and Alzheimer's disease (AD), are protein-misfolding related disorders sharing common pathological mechanisms and the urgent need for efficacious therapies [6,51]. The role played by α-syn in PD has been experimentally investigated using different form of aggregates (oligomers, protofibrils and fibrils).