New knowledge on genetic risk factors and targets for intervention in Parkinson’s disease

Genes contributing to an increased risk for PD include:

An inverse relationship between glucocerebrosidase levels and oligomeric α-synuclein

• the glucocerebrosidase gene, GBA1
• the leucine-rich repeat kinase 2 gene, LRRK2
• the α-synuclein gene, SNCA^1,2

An inverse relationship exists between levels of glucocerebrosidase and oligomeric α-synuclein,³ noted Professor Ellen Sidransky, National Human Genome Research Institute, MD.

LRRK2

Mutant LRRK2 is neurotoxic

LRRK2 is the most common monogenic cause of PD, accounting for 1–5% of cases, said Professor Elisa Greggio, Padova, Italy. LRRK2 PD is similar to sporadic PD phenotypically and in its response to levodopa.⁴

Progressive nigral dopaminergic neuron degeneration is observed in a mammalian LRRK2 G2019S mutation model,⁵ and LRRK2 G2019S kinase activity in human and animal models triggers neurotoxic N-ethylmaleimide sensitive factor (NSF) aggregation,⁶ said Professor Greggio.

LRRK2 regulates lysosomal‐based degradative pathways in neuronal and non‐neuronal cells,⁷ she explained. It is thought that NSF aggregation interferes with catabolism leading to the formation of cytotoxic protein inclusions.⁷

LRRK2 plays a role in lysosomal‐based degradative and inflammatory pathways

LRRK2 also plays a role in inflammatory pathways; and regular use of anti-inflammatory drugs may be associated with reduced penetrance in LRRK2-associated PD.⁸

α-synuclein

α-synuclein is a presynaptic nerve terminal protein that may be involved in membrane transport, but its physiological role is otherwise unknown, said Professor Daniel Otzen, Aarhus, Denmark.⁹ Aggregated α-synuclein is the major constituent of the intraneuronal Lewy bodies associated with PD.¹⁰

α-synuclein oligomers and fibrils are cytotoxic and trigger aggregation

α-synuclein monomers are highly dynamic but conversion into cytotoxic oligomers and fibrils triggers aggregation,¹¹ he explained.

The mechanisms responsible for the conformational changes of α-synuclein are not clear. Future understanding about the factors that promote the formation of monomers, oligomers, and fibrils and α-synuclein aggregation promise to inform the development of biomarker assays and therapies for PD.¹²