Parkinson’s disease (PD) is an extrapyramidal disorder characterized by neuronal degeneration in several regions of the peripheral and central nervous systems. It is the second most frequent neurodegenerative disease after Alzheimer’s. It has become a major health problem, affecting 1% of the world population over 60 years old and 3% of people beyond 80 years. The main histological findings are intracellular Lewy bodies composed of misfolded α-synuclein protein aggregates and loss of dopaminergic neurons in the central nervous system. Neuroinflammation, apoptosis, mitochondrial dysfunction, altered calcium homeostasis, abnormal protein degradation, and synaptic pathobiology have been put forward as mechanisms leading to cell death, α-synuclein deposition, or both. A progressive loss of dopaminergic neurons in the substantia nigra late in the neurodegeneration leads to developing motor symptoms like bradykinesia, tremor, and rigidity. The renin–angiotensin system (RAS), which is involved in regulating blood pressure and body fluid balance, also plays other important functions in the brain. The RAS is involved in the autocrine and paracrine regulation of the nigrostriatal dopaminergic synapses. Dopamine depletion, as in PD, increases angiotensin II expression, which stimulates or inhibits dopamine synthesis and is released via AT1 or AT2 receptors. Furthermore, angiotensin II AT1 receptors inhibit D1 receptor activation allosterically. Therefore, the RAS may have an important modulating role in the flow of information from the brain cortex to the basal ganglia. High angiotensin II levels might even aggravate neurodegeneration, activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which leads to increased reactive oxygen species production.

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The genetic basis of Neurogenic Orthostatic Hypotension (NOH) in Parkinson’s disease (PD) has been inadequately explored. In a cross-sectional study, we examined the association between NOH and PD-related single-nucleotide polymorphisms (SNPs) and mapped their effects on gene expression and metabolic and signaling pathways. Patients with PD, free from pathological conditions associated with OH, and not taking OH-associated medications were included. NOH was defined as per international guidelines. Logistic regression was used to relate SNPs to NOH. Linkage-disequilibrium analysis, expression quantitative trait loci, and enrichment analysis were used to assess the effects on gene expression and metabolic/signaling pathways. We included 304 PD patients in the study, 35 of whom had NOH (11.5%). NOH was more frequent in patients with SNPs in SNCA, TMEM175, FAM47E-STBD1, CCDC62, SCN3A, MIR4696, SH3GL2, and LZTS3/DDRGK1 and less frequent in those with SNPs in ITGA8, IP6K2, SIPA1L2, NDUFAF2. These SNPs affected gene expression associated with the significant hierarchical central structures of the autonomic nervous system. They influenced several metabolic/signaling pathways, most notably IP3/Ca++ signaling, the PKA-CREB pathway, and the metabolism of fatty acids. These findings provide new insights into the pathophysiology of NOH in PD and may provide targets for future therapies.

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Based on clinical and experimental evidence, metabolic syndrome (MetS) and type 2 diabetes (T2D) are considered risk factors for chronic cerebral hypoperfusion (CCH) and neurodegeneration. Scientific evidence suggests that protein misfolding is a potential mechanism that explains how CCH can lead to either Alzheimer’s disease (AD) or vascular cognitive impairment and dementia (VCID). Over the last decade, there has been a significant increase in the number of experimental studies regarding this issue. Using several animal paradigms and different markers of CCH, scientists have discussed the extent to which MetSor T2D causes a decrease in cerebral blood flow (CBF). In addition, different models of CCH have explored how long-term reductions in oxygen and energy supply can trigger AD or VCID via protein misfolding and aggregation. Research that combines two or three animal models could broaden knowledge of the links between these pathological conditions. Recent experimental studies suggest novel neuroprotective properties of protein-remodeling factors. In this review, we present a summarized updated revision of preclinical findings, discussing clinical implications and proposing new experimental approaches from a translational perspective. We are confident that research studies, both clinical and experimental, may find new diagnostic and therapeutic tools to prevent neurodegeneration associated with MetS, diabetes, and any other chronic non-communicable disease (NCD) associated with diet and lifestyle risk factors.

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