The role of mitochondria in reduced penetrance of heterozygous Parkin mutations
Creators: name: Castelo Rueda, Maria Paulina
Publisher: name: Universit� degli studi di Trento
Year: 2021

description: Parkinson�s Disease (PD) is the most common neurodegenerative movement disorder, estimated to affect up to 2% of the population over 65 years of age (Lin et al., 2019; Santos et al., 2019). Parkin (PRKN) mutations are the most common known cause of autosomal recessive early-onset PD, accounting for up to 77% of cases with an age of onset ?20 years (Lucking et al., 2000), and parkin dysfunction represents a risk factor for sporadic PD (Dawson &amp; Dawson, 2014). Parkin variants have been identified in numerous families with different genetic backgrounds (Hedrich et al., 2004) and include more than 170 mutations consisting of copy number variations (deletions or multiplications of exons), small deletions/insertions, as well as single nucleotide polymorphisms (missense, nonsense, or splice site variations) (Corti et al., 2011). Importantly, a large number of patients carry exon rearrangements that result in protein truncation (Hedrich et al., 2001). Parkin is an E3 ubiquitin ligase, mostly known for its role in facilitating the selective clearance of dysfunctional mitochondria (mitophagy), and for its involvement in several other cellular processes like mitochondrial biogenesis, free radical metabolism, and inflammation (Celardo et al., 2014). Homozygous or compound-heterozygous mutations in the Parkin gene result in highly penetrant symptom expression, while heterozygous mutations have been predicted to predispose to disease symptoms with highly reduced penetrance (Huttenlocher et al., 2015; Weissbach et al., 2017). The presence of heterozygous Parkin mutations is one of the reported potential genetic risk factors for PD; (Huttenlocher et al., 2015; Klein et al., 2007). Considering the reported frequency of heterozygous mutations in the population (up to 3%), it is essential to have better estimates of the penetrance of these variants, and to investigate which risk markers manifest in carriers and are potentially useful for identifying those individuals at greater risk of neurodegeneration later in life. Furthermore, it is of great importance to test the causal link between heterozygous pathogenic mutations in Parkin and expressivity of molecular phenotypes in cellular models derived from mutation carriers. This was addressed in this thesis by (1) identifying Parkin mutation carriers in the population-based CHRIS study and characterizing them for the presence of PD risk markers; and (2) by evaluating mitochondrial integrity, including mitochondrial DNA variation and mitochondrial function, in diverse cellular models of heterozygous Parkin mutation carriers. I was able to show that heterozygous Parkin mutation carriers in the general population have increased occurrence of diabetes and decreased heart rate. Moreover, in a subset of individuals, I have identified an altered molecular phenotype, characterized by disparities at the level of mtDNA integrity and mitochondrial function in blood and two different cellular models derived from the mutation carriers. To adequately understand individual disease conversion, there is a need for more longitudinal studies with putatively healthy individuals carrying Parkin mutations and more in-depth clinical phenotyping.