LRRK2 and idiopathic Parkinson's disease
Emily M Rocha1, Matthew T Keeney2, Roberto Di Maio1
1Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Trends in Neurosciences
|January 7, 2022
Summary
Leucine-rich repeat kinase-2 (LRRK2) activation, influenced by genetics and environment, plays a key role in idiopathic Parkinson's disease (iPD) pathogenesis, even without mutations. This highlights LRRK2's central role in iPD.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Idiopathic Parkinson's disease (iPD) has multifactorial causes, including genetic and environmental factors.
- Mutations in leucine-rich repeat kinase-2 (LRRK2) are a common cause of autosomal dominant Parkinson's disease (PD).
- The role of LRRK2 in iPD, independent of mutations, is not fully understood.
Purpose of the Study:
- To review how LRRK2 architecture influences kinase activation.
- To explore the contribution of enhanced LRRK2 substrate phosphorylation to PD pathogenesis.
- To examine how non-mutated LRRK2 is activated in iPD.
Main Methods:
- Literature review on LRRK2 structure-function relationships.
- Analysis of LRRK2 activation mechanisms.
- Examination of LRRK2's role in response to oxidative stress, endolysosomal dysfunction, and environmental toxicants.
Main Results:
- LRRK2 architecture dictates kinase activation.
- Oxidative stress and endolysosomal dysfunction activate non-mutated LRRK2 in iPD.
- Environmental toxicants linked to iPD risk also activate LRRK2.
Conclusions:
- Enhanced LRRK2 substrate phosphorylation may contribute to iPD pathogenesis.
- Non-mutated LRRK2 activation by cellular stress and environmental factors is comparable to pathogenic mutations.
- Evidence strongly suggests a significant role for LRRK2 in the development of idiopathic Parkinson's disease.
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