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Review
. 2021 Apr 19;27(1):42.
doi: 10.1186/s10020-021-00281-8.

Genotype-driven therapeutic developments in Parkinson's disease

Jannik Prasuhn  1   2   3 , Norbert Brüggemann  4   5   6
Affiliations
Review

Genotype-driven therapeutic developments in Parkinson's disease

Jannik Prasuhn et al. Mol Med. .

Abstract

Background: Remarkable advances have been reached in the understanding of the genetic basis of Parkinson's disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches. These genetic findings have led to an imminent progress towards pathophysiology-targeted clinical trials and potentially disease-modifying treatments in the future.

Main body of the manuscript: In this review article we will summarize known genetic contributors to the pathophysiology of Parkinson's disease, the molecular mechanisms leading to disease development, and discuss challenges and opportunities in clinical trial designs.

Conclusions: The future success of clinical trials in PD is mainly dependent on reliable biomarker development and extensive genetic testing to identify genetic cases. Whether genotype-dependent stratification of study participants will extend the potential application of new drugs will be one major challenge in conceptualizing clinical trials. However, the latest developments in genotype-driven treatments will pave the road to individualized pathophysiology-based therapies in the future.

Keywords: GBA; Genetic; LRRK2; Monogenic; PINK1; PRKN (Parkin); Parkinson’s disease; SNCA; Therapy; Translational; Treatment.

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Conflict of interest statement

The authors declare that there are no competing interests to report.

Figures

Fig. 1
Fig. 1
Converging pathways in Parkinson’s disease pathophysiology and relevant genes associated. The main disease mechanisms and current drug targets for mPD and GBA-PD are summarized. The links between key pathophysiological aspects are highlighted with double arrows indicating that translational therapies targeting related pathways may also be of use for a plethora of mPD, GBA-PD and IPD cases. Panel A depicts the aggregation of monomeric to oligomeric α-synuclein aggregates resulting in the formation of Lewy's bodies. Panel B.I and B.II symbolize endosomal disturbances, resulting in impaired neurotransmitter release (in particular VPS35) or impaired degradation of complex molecule structures by autophagy. Panel C illustrates mitochondrial damage, e.g., caused by oxidative stress (highlighted with thunderbolts), which can result in impaired mitochondrial dynamics (fusion and fission processes) among other downstream effects. ATP13A2: ATPase Cation Transporting 13A2. DNAJC13: DnaJ Heat Shock Protein Family (Hsp40) Member C13. DNAJC6: DnaJ Heat Shock Protein Family (Hsp40) Member C6. FBXO7: F-Box only protein 7. GBA: Glucosylceramidase Beta. GBA-PD: GBA-associated Parkinson’s disease. LRRK2: Leucine Rich Repeat Kinase 2. mPD: monogenic Parkinson’s disease. PARK7: oncogene DJ-1. PINK1: PTEN-induced kinase 1. PLA2G6: Phospholipase A2 Group VI. POLG: Mitochondrial Polymerase Gamma. PRKN: Parkin. SNCA: α-synuclein. SYNJ1: Synaptojanin 1. VPS13C: Vacuolar Protein Sorting 13 Homolog C. VPS35: VPS35 Retromer Complex Component
See this image and copyright information in PMC

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