Pathogenic mechanisms of LRRK2 mutations

/Abstract Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial Parkinson’s disease (PD) with Lewy body and/or tau pathologies and are also associated with idiopathic PD, dementia with Lewy bodies (DLB), and tauopathies. Despite the importance, pathogenic mechanisms of LRRK2 mutations remain unresolved. Because of early discoveries that LRRK2 mutations increase its kinase activity, over the past two decades major pharmaceutical companies and academic labs worldwide have focused on the development of kinase inhibitors. However, LRRK2 has several other functional domains, suggesting that it has additional functions beyond kinase. Furthermore, our genetic studies revealed unexpectedly that LRRK2 and its functional homologue LRRK1 play an overlapping, essential physiological role in the protection of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA terminals in the striatum during aging. Moreover, development and multidisciplinary analysis of DA neuron-specific conditional knockout mice further demonstrated that this critical, relevant physiological role is cell autonomous to DA neurons in the SNpc, highlighting the importance of LRRK2 in protecting DA neurons from degeneration in the aging brain. These findings suggested that pathogenic mechanisms of LRRK2 mutations might be more complex than simply enhancing kinase activity. Importantly, there has been no experimental evidence demonstrating that increased LRRK2 kinase activity causes DA neurodegeneration in the aging brain. In this application, we propose to investigate whether mitochondrial and/or autophagy-lysosomal dysfunction underlies LRRK2-dependent DA neuronal survival in a cell autonomous or non-cell autonomous manner. We will further investigate the impact of two unique, important LRRK2 mutations, R1441C and G2019S, using the physiologically relevant knockin alleles compared to the null alleles, on DA neuronal survival during aging, mitochondrial and autophagy-lysosomal function in DA and cortical neurons, and whether LRRK2 mutations affect cognition, synaptic plasticity, and mitochondrial calcium homeostasis in the cerebral cortex. Completion of the proposed studies will test whether increased kinase activity by LRRK2 mutations causes DA neurodegeneration and will provide new insights into pathogenic mechanisms of LRRK2 mutations in these human diseases as well as LRRK2-based therapeutic development. Project Number: 1R01NS148118-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jie Shen | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $557,883 | Activity Code: R01 | Study Section: Neural Oxidative Metabolism and Death Study Section[NOMD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11339888