New publication on mitochondrial dysfunction and Parkinson's disease
We identified potential presymptomatic molecular markers in clinically non-manifesting heterozygous PRKN variant carriers that could be used to monitor heterozygous PRKN variant carriers during the prodromal phase.
To date, several genes implicated in familial forms of Parkinson's disease (PD) have been reported, including PRKN (Parkin) involved in the regulation of mitochondrial function. Disruption of mitochondrial function has also been highlighted as a key mechanism of Parkinson's disease. The heterozygous variants in PRKN are common variants and may predispose to PD with highly reduced penetrance, through altered mitochondrial function.
Therefore, it is important to test for mitochondrial alteration in cells derived from carriers of pathogenic heterozygous variants to establish potential presymptomatic molecular markers.
In a study just published in Npj Parkinson’s disease, we generated lymphoblasts and human induced pluripotent stem cell (hiPSC)-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality.
We detected hyperactive mitochondrial respiration in lymphoblasts; hiPSC-derived neurons of non-manifesting heterozygous variant carriers also displayed several phenotypes of altered mitochondrial function.
The study results identify molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase. Such markers might also be useful to identify individuals at greater risk of eventual disease development and for testing potential mitochondrial function-based neuroprotective therapies before neurodegeneration advances.
Parkinson´s disease (PD) is a neurodegenerative movement disorder, with both genetic and environmental factors playing an important role in disease onset, and age being the biggest risk factor for developing the disease. Parkinson´s disease is clinically characterized by cardinal motor manifestations, which are often preceded by non-motor symptoms for years or even decades. Even though most PD cases are classified as sporadic, a minority of cases (~10%) have a clear monogenic, autosomal dominant, or recessive, inheritance pattern. PRKN-linked PD is the most common form of early-onset PD across all ethnic groups, representing about 10–20% of cases with the age of onset from 40–50 years and up to 42.2% of cases with an age of onset ≤20 years.
Read the full article here: https://www.nature.com/articles/s41531-023-00499-9
The CHRIS study is a collaborative effort between the Eurac Research Institute for Biomedicine and the Healthcare System of the Autonomous Province of Bozen/Bolzano (Südtiroler Sanitätsbetrieb/Azienda Sanitaria dell’Alto Adige). We thank all study participants from the middle and upper Vinschgau/Val Venosta, the general practitioners, and the personnel of the Hospital of Schlanders/Silandro for their support and collaboration. Furthermore, we thank the study assistants and the biobank of the Institute for Biomedicine for data and sample collection and elaboration.
The CHRIS biobank was assigned the “Bioresource Research Impact Factor” (BRIF) code BRIF6107. The CHRIS study is funded by the Department of Innovation, Research and the University of the Autonomous Province of Bozen/Bolzano, Italy.
This research was funded by the Department of Innovation, Research and University of the Autonomous Province of Bozen/Bolzano, Italy, through a core funding initiative to the Institute for Biomedicine and by the Deutsche Forschungsgemeinschaft to A.A.H., A.G., C.K., and P.P.P. (FOR2488). Moreover, A.G. was supported by the Luxembourg National Research Fund within the framework of the INTER (ProtectMove, INTER/DFG/19/14429377) and ATTRACT (Model-IPD, FNR9631103) programs. The authors thank the Department of Innovation, Research and University of the Autonomous Province of Bozen/Bolzano for covering the Open Access publication costs.
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