Alpha-Synuclein Pathology in the Submandibular Gland of LRRK2 p.G2019S Mutation Carriers.

Abstract

Background. The presence of intraneuronal aggregates of phosphorylated alpha-synuclein (pAS), the histological hallmark of Parkinson disease (PD), has been already demonstrated to be present in the autonomic nerve fibres that innervate the submandibular gland in approximately 75% of living PD patients. The presence of pAS in the peripheral autonomic nervous system in carriers of LRRK2 mutations has not been studied so far. The objective of the current study is to evaluate the presence of abnormal pAS aggregates in the submandibular gland tissue of LRRK2 p.G2019S mutations carriers.Methods. This is a prospective observational study conducted between 2014 and 2015 at Hospital Clínic de Barcelona, Spain. A random sample of nine asymptomatic LRRK2 (aLRRK2) and 11 LRRK2 associated PD (LRRK2-PD) patients were recruited among a cohort of LRRK2-PD patients and their relatives already identified at our centre. All the participants underwent transcutaneous needle core biopsy of the submandibular gland under ultrasound guidance. The presence of pAS was assessed in all the participants by immunohistochemistry using anti-Serine 129-phosphorylated AS antibody.Results. Submandibular biopsy material containing glandular parenchyma was obtained in 4 (44.44%) aLRRK2 and in 6 (54.55%) LRRK2-PD patients. Aggregates of pAS were detected in the glandular parenchyma in one of the four (25%) aLRRK2 subjects and in none (0%) of the LRRK2-PD patients. Conclusions. Our study shows that pAS aggregates obtained by needle core biopsy of the submandibular gland are infrequent in LRRK2 mutation carriers but may be detected in asymptomatic mutation carriers. The low rate of pAS positive biopsies suggests either a different physiopathology between LRRK2-related and idiopathic PD or that a one-time unilateral submandibular gland biopsy is not the optimal procedure for the study of synuclein aggregation in LRRK2 mutation carriers.

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

“…Of note, α-Syn and post translational modified α-Syn in peripheral and accessible tissues have been investigated as possible biomarkers for the diagnosis of PD and other synucleinopathies. Nevertheless, since none of them has been validated across different cohorts so far, we still miss a clear cut evidence supporting their factual clinical significance (Witt et al, 2009;Pouclet et al, 2012;Shannon et al, 2012;Donadio et al, 2014Donadio et al, , 2018Sprenger et al, 2015;Zange et al, 2015;Stokholm et al, 2016;Vilas et al, 2016;Fereshtehnejad et al, 2017).…”

“…The fact that α-Syn can be found in different forms (monomeric, oligomeric, aggregated or post translational modified) in accessible and peripheral tissues such as CSF, blood, saliva, tears, colon, esophagus and skin (Tokuda et al, 2010;Devic et al, 2011;Foulds et al, 2011Foulds et al, , 2012Mollenhauer et al, 2013;Abd-Elhadi et al, 2015;Koehler et al, 2015;Chung et al, 2016;Cariulo et al, 2019;Fenyi et al, 2019;Hamm-Alvarez et al, 2019;Vivacqua et al, 2019;Maass et al, 2020;Wang et al, 2020b;Tanei et al, 2021;Bakhit et al, 2022), opened up the possibility to evaluate whether these different proteoforms may be useful for the diagnosis of PD and or other synucleinopathies (Witt et al, 2009;Pouclet et al, 2012;Shannon et al, 2012;Donadio et al, 2014Donadio et al, , 2018Sprenger et al, 2015;Zange et al, 2015;Stokholm et al, 2016;Vilas et al, 2016;Fereshtehnejad et al, 2017;Fayyad et al, 2019;Parnetti et al, 2019;Vivacqua et al, 2019Vivacqua et al, , 2023Wang et al, 2020b;Ganguly et al, 2021).…”

Trends and hotspots in non-motor symptoms of Parkinson’s disease: a 10-year bibliometric analysis

“…Regarding biomarkers of PD, the formation of Lewy bodies and neural inclusions in the form of Lewy neuromasts by aggregation and misfolding of α-syn are the main pathological products of PD. As diagnostic biomarkers continue to progress, α-syn in new tissue and fluid specimens such as cerebrospinal fluid (Shahnawaz et al, 2017), blood (Abd-Elhadi et al, 2015), salivary glands (Vilas et al, 2016), and skin (Donadio et al, 2014;Wang et al, 2021) may serve as biomarkers of the prodromal disease stage (Tolosa et al, 2021). Novel MRI techniques, including neuromelanin imaging, quantitative susceptibility mapping (QSM), and visual assessment of dorsal nigrostriatal high signals, have the potential to assess nigrostriatal pathology in PD and have been a major focus of recent research efforts (Murakami et al, 2015;Wang et al, 2019).…”