Somatische Modifikatoren des erblichen Parkinsonismus

• Applicant: Privatdozentin Joanne Trinh, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544202071

X-linked dystonia-parkinsonism (XDP) is endemic to the Philippines and characterized by adulthood-onset dystonic movements and parkinsonism due to striatal volume loss as a result of an insertion of the retrotransposon SVA in intron 32 of the TAF1 gene. XDP is one of a large, ever-growing class of ~50 diseases caused by unstable tandem repeats and, in particular, a sub-class of inserted repeats. My group has recently identified a completely novel modifier in XDP, a repeat interruption that exists in somatic mosaic form. This mosaic modifier exists both in blood and brain. We coined the new term mosaic divergent repeat interruptions affecting both motif length and sequence (mDRILS) of the canonical motif polarized within the expanded SINE-VNTR-Alu(AGAGGG)n repeat of TAF1. A specific mDRILS is found to be protective for age at onset (AAO), and its presence increases repeat stability. Still, further investigation of how this mosaic mechanism is transmitted across generations in families with XDP and how it behaves in cellular models is warranted. The mDRILS identified within XDP solidifies the status of it being a model disease to study genetic modifiers. The somatic genetic factors found within XDP have the potential to be generalizable into other forms of parkinsonism. We now hypothesize that mDRILS modify generational onset in XDP families, change over time in blood, are present in cellular models and brain tissue, and somatic mosaicism may also be observed in forms of Parkinson’s disease. We aim to use long-read sequencing and optical mapping to assess familial transmission of repeat length and mDRILS in blood-derived DNA from multiple XDP families, stability of mDRILS longitudinally over sampling time points in cellular models and brain regions, and determine if somatic variants affect PD risk. Finding a novel genetic basis of disease has large potential for identifying lifestyle factors that affect somatic load, and looking into newly nominated genes with somatic variants for disease pathways. These genetic modifiers for hereditary forms of parkinsonism will aid in individual patient counseling and, eventually, inform new treatment approaches in the context of personalized medicine.

• DFG Programme: Research Grants