DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration

Individuazione di nuovi biomarker nella Malattia di Parkinson: uno studio su biopsie gastrointestinali

In Parkinson’s Disease (PD), several evidence indicates the involvement of gut-brain axis as one of the primary physio-pathological mechanisms underlying α-Syn aggregation and following propagation to CNS. In this regard, pathological α-Syn may be a candidate PD biomarker for its role in PD pathophysiology and its expression in several peripheral tissues, most importantly in enteric nervous system. Furthermore, gastrointestinal dysfunctions represent one of the main non-motor symptoms in PD, often preceding the development of proper motor symptoms. Our aim was to investigate as ne biomarker α-Syn aggregation through specific antibodies and seeding activity in stomach-duodenum biopsies of PD patients by real-time quaking induced conversion (RT-QuIC) assay. The αSyn RT-QuIC assay follow the seeded aggregation of monomeric αSyn into amyloid fibrils upon seeding by traces of αSyn aggregates present in biospecimens. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique originally introduced for prion diseases diagnosis that can detect minute amounts of amyloidogenic proteins in cerebrospinal fluid (CSF) or other biospecimens, taking advantage of their ability to trigger a protein self-aggregation. Recently, the assay was successfully adapted to detect α-Syn seeds in biofluid and tissues in patients with PD. We found a relevant α-Syn aggregated protein with 5G4 antibody and seeding activity in almost all biopsies of PD patients, with higher response in the duodenum biopsies than stomach and minimum activity were detected in the control biopsies. The enteric nervous system could be one of the earliest implicated structures in the processes of α-Syn aggregation and an unmet clinical need is a reliable early diagnostic biomarker for Parkinson’s disease. We suggest that the combination of endoscopic biopsy of the gastric and duodenal mucosa to the high sensitivity of the 5G4 IHC and RT-QuIC assay in the detection of α-Syn seeding activity could to be an helpful new biomarker to evaluate early stages of PD. In conclusion, our data suggest that duodenal biopsy may represent a safe, feasible and useful tool for characterizing PD GI pathology and discerning patients from controls. Future studies will be required to confirm these findings in in a prodromal or early PD phase and to evaluate subjects with other synucleinopathies in particular multiple system atrophy.In Parkinson’s Disease (PD), several evidence indicates the involvement of gut-brain axis as one of the primary physio-pathological mechanisms underlying α-Syn aggregation and following propagation to CNS. In this regard, pathological α-Syn may be a candidate PD biomarker for its role in PD pathophysiology and its expression in several peripheral tissues, most importantly in enteric nervous system. Furthermore, gastrointestinal dysfunctions represent one of the main non-motor symptoms in PD, often preceding the development of proper motor symptoms. Our aim was to investigate as ne biomarker α-Syn aggregation through specific antibodies and seeding activity in stomach-duodenum biopsies of PD patients by real-time quaking induced conversion (RT-QuIC) assay. The αSyn RT-QuIC assay follow the seeded aggregation of monomeric αSyn into amyloid fibrils upon seeding by traces of αSyn aggregates present in biospecimens. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique originally introduced for prion diseases diagnosis that can detect minute amounts of amyloidogenic proteins in cerebrospinal fluid (CSF) or other biospecimens, taking advantage of their ability to trigger a protein self-aggregation. Recently, the assay was successfully adapted to detect α-Syn seeds in biofluid and tissues in patients with PD. We found a relevant α-Syn aggregated protein with 5G4 antibody and seeding activity in almost all biopsies of PD patients, with higher response in the duodenum biopsies than stomach and minimum activity were detected in the control biopsies. The enteric nervous system could be one of the earliest implicated structures in the processes of α-Syn aggregation and an unmet clinical need is a reliable early diagnostic biomarker for Parkinson’s disease. We suggest that the combination of endoscopic biopsy of the gastric and duodenal mucosa to the high sensitivity of the 5G4 IHC and RT-QuIC assay in the detection of α-Syn seeding activity could to be an helpful new biomarker to evaluate early stages of PD. In conclusion, our data suggest that duodenal biopsy may represent a safe, feasible and useful tool for characterizing PD GI pathology and discerning patients from controls. Future studies will be required to confirm these findings in in a prodromal or early PD phase and to evaluate subjects with other synucleinopathies in particular multiple system atrophy

Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease

Parkinson's disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients' brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials

Insight into antioxidant properties of milk‐derived bioactive peptides in vitro and in a cellular model

Milk is a nutritionally important source of bioactive peptides with anti‐inflammatory, immunomodulatory, anticancer, and antioxidant properties. These compounds can be useful as ingredients of functional food. For this reason, in the last decades, bioactive peptides attracted the interest of researchers and food companies. In this work, the results obtained with six milk‐derived bioactive peptides (Y‐4‐R, V‐6‐R, V‐7‐K, A‐10‐F, R‐10‐M, and H‐9‐M) synthesized and studied for their antioxidant properties in vitro and in a cellular model, are reported. These molecules correspond to peptide fragments derived from parent compounds able to cross the apical membrane of Caco‐2 cell layer and released in the basolateral compartment. In vitro, antioxidant tests such as 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid) (ABTS) and crocin bleaching showed antioxidant activity mainly for peptides Y‐4‐R and V‐6‐R, respectively. In Caco‐2 cells, peptides V‐6‐R, H‐9‐R, Y‐4‐R, and particularly R‐10‐M and V‐7‐K are able to prevent the decrease of viability due to oxidative stress. The latter peptide is also the most effective in protecting cells from lipid peroxidation. In conclusion, the reported hydrolyzed peptides are shown to exert the antioxidant properties both in vitro and in a cellular model

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation

Background: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. Case: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. Conclusions: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes