Is serine racemase (SRR) a second hit target for LRRK2-G2019S induced Parkinson’s disease?

Abstract

To date, at least 7 mil l ion people are suffering from Parkinson’s disease (PD) worldwide, which is the second most prevalent, age-associated, and progressive neurodegenerative disorder (Tysnes and Storstein, 2017). Given the accelerated global pace of aging, it becomes of fundamental importance that we start understanding the origins of neurodegeneration in order to develop effective disease modifying treatments . Most PD pat ients suffer from a combination of motor and nonmotor disabilities. The motor symptoms typically manifest in bradykinesia, tremor and rigidity (Hoehn and Yahr, 2001). The physical decline is directly linked to the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which disrupts dopamine signalling responsible for movement and mobility (Lanciego et al., 2012). The non-motor symptoms are more diverse and include depression, anxiety, loss of smell, constipation, sleep disorders, and dementia (Chaudhuri and Schapira, 2009). Some of them precede the motorones by decades, raising the possibility that PD might have a long-term-compensated neurodevelopmental origin, which only manifests at older age and in presence of other contributing factors (Le Grand et al., 2014).