Objective The objective of this study was to outline the dynamics of prokineticin‐2 pathway in relation to clinical‐pathological features of Parkinson's disease by examining olfactory neurons of patients. Methods Thirty‐eight patients (26 de novo, newly diagnosed) and 31 sex/age‐matched healthy controls underwent noninvasive mucosa brushing for olfactory neurons collection, and standard clinical assessment. Gene expression levels of prokineticin‐2, prokineticin‐2 receptors type 1 and 2, and prokineticin‐2‐long peptide were measured in olfactory neurons by real‐time polymerase chain reaction (PCR); moreover, the prokineticin‐2 protein and α‐synuclein species (total and oligomeric) were quantified by immunofluorescence staining. Results Prokineticin‐2 expression was significantly increased in Parkinson's disease. De novo patients had higher prokineticin‐2 levels, directly correlated with Movement Disorder Society‐Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS‐UPDRS) part III motor score. In addition, oligomeric α‐synuclein was higher in Parkinson's disease and directly correlated with prokineticin‐2 protein levels. Total α‐synuclein did not differ between patients and controls. Interpretation Prokineticin‐2 is a chemokine showing neuroprotective effects in experimental models of Parkinson's disease, but translational proof of its role in patients is still lacking. Here, we used olfactory neurons as the ideal tissue to analyze molecular stages of neurodegeneration in vivo, providing unprecedented evidence that the prokineticin‐2 pathway is activated in patients with Parkinson's disease. Specifically, prokineticin‐2 expression in olfactory neurons was higher at early disease stages, proportional to motor severity, and associated with oligomeric α‐synuclein accumulation. These data, consistently with preclinical findings, support prokineticin‐2 as a candidate target in Parkinson's disease, and validate reliability of olfactory neurons to reflect pathological changes of the disease. ANN NEUROL 2023;93:196–204

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis.

Head trauma (HT) is emerging as an event anticipating onset of neurodegenerative disorders. However, the potential contribution of HT in young-onset cases (YOPD, age at onset < 50) of Parkinson’s disease (PD) has not been examined yet. Here, we systematically assessed HT history in PD patients to estimate the risk associated, especially in terms of age of onset, and define the correlations with the clinical-biochemical profile. The Brain Injury Screening Questionnaire (BISQ) was administered to 94 PD patients (31 with YOPD, known monogenic forms excluded) and 70 controls. HT history was correlated with motor and non-motor scores in all patients, and to CSF biomarkers of neurodegeneration (α-synuclein, amyloid-β42, total and phosporiled-181 tau, lactate, CSF/serum albumin) into a subgroup. HT increased the risk for both PD and YOPD. In PD patients, but not in those with YOPD, the number of HTs directly correlated with CSF total-tau levels. No other correlations resulted between HT and clinical parameters. Sport-related HT was a specific risk factor for YOPD; conversely, the prolonged sporting life represented a protective factor. HTs can favor PD onset, even as YOPD. Sport-related HT resulted a risk factor for YOPD, although the longer sporting practice delayed PD onset, protecting from YOPD. Tauopathy may underlie the overall association between HT and PD. Additional mechanisms could be instead implicated in HT contribution to YOPD onset.

Mitochondria are central in the pathogenesis of Parkinson’s disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims to shape the pattern of mitochondrial respiration in the blood leukocytes of PD patients in relation to both clinical features and the profile of cerebrospinal fluid (CSF) biomarkers of neurodegeneration. Mitochondrial respirometry on the peripheral blood mononucleate cells (PBMCs) of 16 PD patients and 14 controls was conducted using Seahorse Bioscience technology. Bioenergetic parameters were correlated either with standard clinical scores for motor and non-motor disturbances or with CSF levels of α-synuclein, amyloid-β peptides, and tau proteins. In PD, PBMC mitochondrial basal respiration was normal; maximal and spare respiratory capacities were both increased; and ATP production was higher, although not significantly. Maximal and spare respiratory capacity was directly correlated with disease duration, MDS-UPDRS part III and Hoehn and Yahr motor scores; spare respiratory capacity was correlated with the CSF amyloid-β-42 to amyloid-β-42/40 ratio. We provided preliminary evidence showing that mitochondrial respiratory activity increases in the PBMCs of PD patients, probably following the compensatory adaptations to disease progression, in contrast to the bases of the neuropathological substrate.

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Systemic comorbidity precipitates the risk for dementia. To comprehend the underlying mechanisms into a therapeutic perspective, we analyzed how comorbidity affects neurodegeneration-related cerebrospinal fluid (CSF) biomarkers of 55 cognitively intact subjects. The Charson Comorbidity Index (CCI) was correlated with CSF amyloid-β42 (Aβ42), amyloid-β40, total-tau, 181-phosphorylated-tau (p-tau), the Aβ42/p-tau ratio, neurogranin, and lactate. The age-related brain lesions at imaging were also considered. CCI had a raw association with Aβ42/p-tau and p-tau, and a stronger, age-independent correlation with lactate. These preliminary findings suggested that, in normal subjects, systemic comorbidity might increase CNS oxidative stress and, together with aging, contribute to develop an Alzheimer’s disease-like biochemical profile.

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