Trends in Genetics
ReviewProgress in unraveling the genetic etiology of Parkinson disease in a genomic era
Section snippets
PD and related disorders
Parkinsonism refers to a group of neurological syndromes presenting with bradykinesia, muscle rigidity, resting tremor, and postural instability. PD, the most common form of parkinsonism, is clinically characterized by these four cardinal motor symptoms as well as a good response to levodopa therapy [1]. Various nonmotor symptoms may present, including depression, sleep disturbances, constipation, orthostatic hypertension, and, in later disease stages, dementia [2]. Neuropathological hallmarks
Disentangling the genetic etiology
For many years, PD was considered a nongenetic disorder caused by synergistic environmental factors. A study estimating the heritability of PD risk in over 500 nuclear families revealed, however, that in up to 60% of idiopathic PD patients the phenotype could be explained by genetic factors [4]. Furthermore, this genetic etiology was shown to be significantly heterogeneous [5]. Currently, PD is considered a multifactorial disease involving numerous genetic and environmental factors.
Confounding factors in gene identification
Although substantial progress has been made toward the elucidation of the complex genetic etiology of PD and related disorders, it has been noticeably slow compared with pure Mendelian diseases. There are many confounding factors that contribute to this relatively slower rate of gene identification. We discuss below two classes of factors – technical and systemic – that present challenges for PD researchers.
Key molecular processes and therapeutic implementations
The identification of parkinsonism genes has been followed by intense molecular research indicating that neuronal death may originate from the interconnection of various processes including endosomal protein sorting and recycling, synaptic transmission, mitochondrial quality control, and lysosome-mediated autophagy. As discussed above, most of the recent gene discoveries converge on abnormal endocytosis and endosome trafficking as key pathomechanisms for PD and related disorders. Genetic
Translating genetic findings to the clinic
Molecular diagnostic testing encompasses systematic screening of patients and at-risk individuals for the presence of pathogenic, so far mostly exonic, variants in known causal genes. Diagnosing PD is not an exact science, as diagnostic accuracy rates at best reach 88% [119]. Molecular diagnoses may complement clinical diagnoses and consequently improve both diagnostic sensitivity and specificity, reducing the diagnostic uncertainty. Furthermore, it enables early diagnosis as well as prenatal
Concluding remarks
The pathological and genetic overlap between PD and Parkinson-plus syndromes suggests that expanding our knowledge of one disease entity might shed light on the other members of this disease continuum. Genetic commonalities have been observed, with MAPT, SNCA, and GBA variability contributing to susceptibility to different Parkinsonian disorders 39, 46, 47, 54, 63, 64, 65, 66. However, family-based gene identification studies and subsequent functional characterization of the encoded proteins
Acknowledgments
Research in the authors’ group is partly funded by the Belgian Science Policy Office Interuniversity Attraction Poles Program, the Flemish Government-initiated Methusalem Excellence program, the Alzheimer Research Foundation, Research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology (IWT), and the University of Antwerp Research Fund, Belgium. A.V. receives a PhD fellowship from the IWT.
Glossary
- Anticipation
- progressively earlier appearance and increased disease severity in successive family generations, often present in families segregating STR expansions.
- Candidate gene association studies
- a case-control study in which genetic variation within a prespecified gene of interest is statistically compared.
- Epigenetics
- transient gene expression controllers that enable rapid biological adaptation, including CpG DNA methylation, post-translational histone modifications, and RNA-associated
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